Dihydropyrazolopyridine compounds and pharmaceutical use thereof

ABSTRACT

The present invention provides dihydropyrazolopyridine compounds represented by the formula (I):  
                 
 
     wherein each symbol is as defined in the specification, optically active forms thereof, and pharmaceutically acceptable salts thereof and hydrates thereof. The compounds of the present invention show a selective and strong inhibitory activity on glycogen synthase kinase-3 beta (GSK-3β), and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications and neurodegenerative diseases or as immunopotentiators.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta (GSK-3β)-inhibitory activity, and use thereof.

BACKGROUND OF THE INVENTION

[0002] It has been reported that glycogen synthase kinase-3 beta (GSK-3β), a protein kinase, is involved in the causes of various diseases as noted in the following.

[0003] Type-II diabetes is a disease in which the insulin reactivity of pancreatic β cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced. GSK-3β acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GSK-3β-inhibitory activity actually lowers glucose in blood by a GSK-3β-inhibitory activity (Proc. Nat. Acad. Sci., 93, 8455 (1996)). Therefore, medicaments having a GSK-3β-inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof.

[0004] The developmental mechanism of Alzheimer's dementia has not yet been elucidated. However, it is considered that amyloid aggregation and neurofibril changes are closely related to the cause of the development. GSK-3β is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons to induce neuronal death (Neurosci. Lett., 128, 195 (1991)). In addition to the above, (3) the direct involvement of GSK-3β in nuronal death through inactivation of pyruvate dehydrogenase by phosphorylation to decrease the production amount of acetylcholine necessary for maintaining cell activity (Proc. Nat. Acad. Sci., 93, 2719 (1996)) has been reported.

[0005] In addition, the effectiveness for AIDS encephalopathia as a neurodegenerative disease other than Alzheimer's dementia has been suggested. Tat, which is a protein produced by HIV virus that causes AIDS, enhances GSK-3β activity in neurons to induce neuronal death (J. Neurochem., 73, 578 (1999)). From the above, GSK-3β inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.

[0006] Lithium and valproic acid, which have anti-manic-depressive activity, have a GSK-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The relationship between anti-manic-depressive activity and GSK-3β inhibitory activity is unclear, but a suppressive activity on glutamic acid toxicity is considered to be partly responsible for maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642 (1998)). Based on the foregoing, GSK-3β inhibitors are considered to be medicaments effective for improving manic-depressive psychosis.

[0007] NF-AT, a transcription factor, is dephosphorylated by calcineurin to increase immunological responses (Science, 275, 1930 (1997)). GSK-3β acts for suppressing immunological function by conversely phosphorylating NF-AT. Therefore, GSK-3β inhibitors are considered to be medicaments effective for immunopotentiation.

[0008] Incidentally, JP-A-3-272189 (invention drawn to an improved synthesis method of mevalolacton intermediates), JP-A-2-275878 (therapeutic agents for hyperlipoproteinemia and atherosclerosis) and JP-A-1-272584 (therapeutic agents for hyperlipoproteinemia) disclose pyrazolo[3,4-b]pyridine compounds wherein the 6-position is either methyl, isopropyl or cyclopropyl. These publications do not disclose or suggest any action of these compounds on GSK-3β or the central nervous system.

[0009] The specifications of JP-A-59-65089, JP-A-59-118786, JP-A-60-56979, JP-A-60-197685 and the like disclose 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods. The present inventors reproduced the following reaction A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo[1,5-a]pyrimidine derivative represented by the formula (V) could be produced. They measured IR, NMR and the melting point of the compound of the formula (V) and found them to be identical with IR, NMR and the melting point described in the specification of this publication. It is therefore concluded that an erroneous structural formula has been disclosed in these publications. In other words, 6-methyl-4-substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate cannot be synthesized according to the methods described in these publications.

[0010] The compound of the above formula (IV) can be synthesized according to the method described in J. Chem. Soc., Perkin Trans. 1, 947 (1996), and this publication discloses methyl 4-(2-chlorophenyl)-6-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and the like.

SUMMARY OF THE INVENTION

[0011] An object of the present invention is to provide novel compounds having a selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3β), and further, medicaments comprising them and pharmaceutical compositions comprising them.

[0012] The present inventors have intensively studied to achieve the above object, and have found that 4,7-dihydropyrazolo[3,4-b]pyridine derivatives have a selective and strong inhibitory activity on GSK-3β, which resulted in the completion of the present invention. That is, the present invention relates to medicaments comprising, as an active ingredient, dihydropyrazolopyridine compounds represented by the following formula (I), which have a GSK-3β-inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.

[0013] The present invention provides the following.

[0014] [1] A dihydropyrazolopyridine compound of the formula (I):

[0015] wherein

[0016] R⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: —COOR⁸ (wherein R⁸ is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s));

[0017] R¹ and R² are the same or different and each is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or. phenylalkyl;

[0018] R³ is

[0019] (1) alkyl or haloalkyl,

[0020] (2) cycloalkyl,

[0021] (3) phenyl optionally having substituent(s),

[0022] (4) aromatic heterocyclic group,

[0023] (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,

[0024] (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or

[0025] (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent(s), or

[0026] a group selected from the groups represented by the following formulas (II) and (III):

[0027] wherein R⁶ and R⁷ are each phenyl optionally having substituent(s) or an aromatic heterocyclic group,

[0028] or R² and R³ in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s);

[0029] R⁴ is alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), cyano or nitro; and

[0030] R⁵ is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring; or

[0031] phenylaminoalkyl,

[0032] acyl,

[0033] acylalkyl,

[0034] aminocarbonyl,

[0035] arylaminocarbonyl,

[0036] a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s),

[0037] a saturated 3 to 7 membered carbocyclic ring having substituent(s),

[0038] alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or

[0039] a group of the formula: —(CR^(a)R^(b))_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R^(a) is hydrogen or alkyl, R^(b) is hydrogen or alkyl, R¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R¹² is hydrogen or alkyl,

[0040] or R⁴ and R⁵ in conjunction may form a 5 or 6 membered ring optionally containing heteroatom(s),

[0041] provided that when R⁰, R¹ and R² are each hydrogen, R⁴ is methoxycarbonyl and R⁵ is methyl, then R³ should not be phenyl, 2-chloropheny, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R⁵ is alkyl, then R⁴ is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro,

[0042] or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0043] [2] The dihydropyrazolopyridine compound of the above-described [1], wherein

[0044] R⁰ is hydrogen, alkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: —COOR⁸ (wherein R⁸ is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s));

[0045] R¹ and R² are the same or different and each is hydrogen, alkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl;

[0046] R³ is

[0047] (1) alkyl or haloalkyl,

[0048] (2) cycloalkyl,

[0049] (3) phenyl optionally having substituent(s),

[0050] (4) aromatic heterocyclic group,

[0051] (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,

[0052] (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or

[0053] (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring,

[0054] wherein the groups of (2) to (7) may have one or more substituent(s), or

[0055] a group selected from the groups represented by the following formulas (II) and (III):

[0056] wherein R⁶ and R⁷ are each phenyl optionally having substituent(s) or an aromatic heterocyclic group,

[0057] or R² and R³ in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s);

[0058] R⁴ is alkoxycarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro; and

[0059] R⁵ is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring,

[0060] or R⁴ and R⁵ in conjunction may form a 5 or 6 membered ring optionally containing heteroatom(s),

[0061] provided that when R⁰, R¹ and R² are each hydrogen, R⁴ is methoxycarbonyl and R⁵ is methyl, then R³ should not be phenyl, 2-chloropheny, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl,

[0062] or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0063] [3] The dihydropyrazolopyridine compound of the above-described [2], wherein R⁵ is alkyl having 2 to 8 carbon atoms, cycloalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, phenyl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0064] [4] The dihydropyrazolopyridine compound of the above-described [2], wherein R¹ is hydrogen, alkyl, phenyl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0065] [5] The dihydropyrazolopyridine compound of the above-described [2], wherein R² is hydrogen or alkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0066] [6] The dihydropyrazolopyridine compound of the above-described [2], wherein R³ is phenyl optionally having 1 to 3 substituent(s), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0067] [7] The dihydropyrazolopyridine compound of the above-described [2], wherein R⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, cyano or nitro, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0068] [8] The dihydropyrazolopyridine compound of the above-described [2], wherein R⁵ is alkyl having 2 to 4 carbon atoms, cyclopropyl, phenyl, thienyl or hydroxyalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0069] [9] The dihydropyrazolopyridine compound of the above-described [2], wherein R² and R³ in conjunction form a ring containing sulfur atom and the ring is condensed with a benzene ring optionally having substituent(s), or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0070] [10] The dihydropyrazolopyridine compound of the above-described [2], wherein R⁰ is hydrogen or a group of the formula: —COOR⁸ (wherein R⁸ is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)), or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0071] [11] The dihydropyrazolopyridine compound of the above-described [2], which is selected from the group consisting of

[0072] (32) ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0073] (47) ethyl 4-(2-chloro-3-trifluoromethylphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0074] (66) ethyl 4,7-dihydro-4-(naphthalen-1-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0075] (73) ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0076] (87) ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0077] (116) ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0078] (122) 4-(2,3-dichlorophenyl)-4,7-dihydro-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine,

[0079] (140) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine,

[0080] (147) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine,

[0081] (158) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine,

[0082] (171) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine,

[0083] (182) ethyl 4-(2-bromo-3-nitrophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0084] (183) ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0085] (189) 4-(2-bromo-3-nitrophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine,

[0086] (205) ethyl 2-tert-butoxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0087] (240) ethyl 4-(2,1,3-benzoxadiazol-4-yl)-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate,

[0088] (257) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-hydroxymethyl-2H-pyrazolo[3,4-b]pyridine,

[0089] (260) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazol[3,4-b]pyridine,

[0090] (264) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine, and

[0091] (268) 4-(2-bromo-3-cyanophenyl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine,

[0092] a tautomer, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0093] [12] The dihydropyrazolopyridine compound of the above-described [1], wherein

[0094] R⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: —COOR⁸ (wherein R⁸ is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s));

[0095] R¹ is hydrogen;

[0096] R² is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl;

[0097] R³ is

[0098] (1) alkyl or haloalkyl,

[0099] (2) cycloalkyl,

[0100] (3) phenyl optionally having substituent(s),

[0101] (4) aromatic heterocyclic group,

[0102] (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,

[0103] (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or

[0104] (7) a group derived from a 5 to 7 membered saturated. or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring,

[0105] wherein the groups of (2) to (7) may have one or more substituent(s), or

[0106] a group selected from the groups represented by the following formulas (II) and (III):

[0107] wherein R⁶ and R⁷ are each phenyl optionally having substituent(s) or an aromatic heterocyclic group,

[0108] or R² and R³ in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s);

[0109] R⁴ is alkoxycarbonyl,

[0110] alkylcarbonyl,

[0111] alkylsulfonyl,

[0112] alkylsulfinyl,

[0113] phenylsulfinyl,

[0114] phenylsulfonyl,

[0115] dialkylphosphinyl,

[0116] dialkylphosphonyl,

[0117] phenyl optionally having substituent(s),

[0118] an aromatic heterocyclic group optionally having substituent(s),

[0119] cyano or

[0120] nitro; and

[0121] R⁵ is alkyl,

[0122] phenylaminoalkyl,

[0123] acyl,

[0124] acylalkyl,

[0125] aminocarbonyl,

[0126] arylaminocarbonyl,

[0127] a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s),

[0128] a saturated 3 to 7 membered carbocyclic ring having substituent(s),

[0129] alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or

[0130] a group of the formula: —(CR^(a)R^(b))^(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R^(a) is hydrogen or alkyl, R^(b) is hydrogen or alkyl, R¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R¹² is hydrogen or alkyl,

[0131] provided that when R⁰, R¹ and R² are each hydrogen, R⁴ is methoxycarbonyl and R⁵ is methyl, then R³ should not be phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R⁵ is alkyl, then R⁴ is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro,

[0132] or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0133] [13] The dihydropyrazolopyridine compound of the above-described [12], wherein

[0134] R⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group having substituent(s), cyano or nitro, and

[0135] R⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: —(CH₂)_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R¹² is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0136] [14] The dihydropyrazolopyridine compound of the above-described [12] or [13], wherein R² is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0137] [15] The dihydropyrazolopyridine compound of the above-described [12] or [13], wherein R³ is phenyl optionally having 1 to 3 substituent(s), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0138] [16] The dihydropyrazolopyridine compound of the above-described [12] or [13], wherein R⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0139] [17] The dihydropyrazolopyridine compound of the above-described [12] or [13], wherein R⁵ is a group of the formula: —(CH₂)_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R¹¹ is hydrogen, alkyl or alkoxycarbonyl and R¹² is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0140] [18] The dihydropyrazolopyridine compound of the above-described [12] or [13], wherein R⁰ is hydrogen or a group of the formula: —COOR⁸ (wherein R⁸ is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)), or an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0141] [19] The dihydropyrazolopyridine compound of the above-described [12] or [13], which is selected from the group consisting of

[0142] (1002) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0143] (1003) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0144] (1011) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine,

[0145] (1014) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine,

[0146] (1023) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N,N-dimethylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine,

[0147] (1027) 6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2,1,3-5-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine,

[0148] (1033) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-ethylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0149] (1037) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0150] (1038) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0151] (1041) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine,

[0152] (1046) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine,

[0153] (1048) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine,

[0154] (1051) 6-(1-acetylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine,

[0155] (1052) 6-(1-benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine,

[0156] (1053) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0157] (1059) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine,

[0158] (1062) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine,

[0159] (1063) 6-acetylmethyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine,

[0160] (1073) 5-cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine,

[0161] (1075) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-6-carboxylic acid phenylamide,

[0162] (1078) 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(4-phenyl-piperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine,

[0163] (1081) 6-acetyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine,

[0164] (1082) 6-acetyl-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine,

[0165] (1084) 4-(2-bromo-3-cyanophenyl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine,

[0166] (1086) 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(pyrrolidin-3-yl)-2H-pyrazolo[3,4-b]pyridine, and

[0167] (1087) 4-(2,1,3-benzoxadiazol-4-yl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine,

[0168] a tautomer thereof, an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0169] [20] A medicament comprising a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0170] [21] A medicament comprising a dihydropyrazolopyridine compound of the above-described [12] or [13], an optically active form thereof, or a pharmaceutically acceptable salt thereof.

[0171] [22] A pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.

[0172] [23] A pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described [12] or [13], an optically active form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0173] [24] A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof.

[0174] [25] A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described [12] or [13], an optically active form thereof and a pharmaceutically acceptable salt thereof.

[0175] [26] The medicament of the above-described [20] or [21], which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.

[0176] [27] The medicament of the above-described [20] or [21], which is used for prevention and/or treatment of a neurodegenerative disease.

[0177] [28] The medicament of the above-described [27], wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic-depressive psychosis.

[0178] [29] The medicament of the above-described [20] or [21], which is used for prevention and/or treatment of diabetes and diabetic complications.

[0179] [30] The medicament of the above-described [20] or [21], which is used as an immunopotentiator.

[0180] [31] The medicament of the above-described [20] or [21], which is used for prevention and/or treatment of alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell lukemia or virus-induced tumors.

BRIEF DESCRIPTION OF THE DRAWINGS

[0181]FIG. 1 shows the GSK-3β-inhibitory activity of the compounds of Example 47 and Example 137.

[0182]FIG. 2 shows the effect of the compound of Example 66 on amyloid β-induced cytotoxicity.

[0183]FIG. 3 shows the GSK-3β-inhibitory effect of the compound of Example 27 in a gerbil brain ischemia model.

DETAILED DESCRIPTION OF THE INVENTION

[0184] The formula (I) indicates the presence of tautomers represented by the following formulas (I-a) and (I-b), based on the positions of hydrogen atoms of the pyrazole ring. The present invention encompasses each isomer of the formulas (I-a) and (I-b), and a mixture of these isomers.

[0185] The compounds represented by the formula (I) in the present specification are described in detail in the following.

[0186] “Alkyl” means a linear or branched (hydro)carbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl (i.e., amyl), hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with a preference for alkyl having 1 to 4 carbon atom(s). The alkyl of R² is preferably alkyl having 1 to 4 carbon atoms. The alkyl of R⁵ is preferably alkyl having 2 to 8 carbon atoms. The “alkyl having 2 to 8 carbon atoms” concretely includes ethyl, propyl, butyl, pentyl (i.e., amyl), hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like. Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.

[0187] “Acyl” means C₂-C₁₄ acyl, and includes “alkylcarbonyl” having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, at R⁴ preferably having 2 to 5 carbon atoms, and aromatic acyl having 7 to 12 carbon atoms including “C₇-C₁₂ arylcarbonyl” such as benzoyl, naphthoyl and the like and “C₇-C₁₂ aralkylcarbonyl” such as benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, cinnamoyl, and the like, and the like. The benzene and naphthalene rings may have 1 to 5 substituent(s) and substitution sites are not particularly limited.

[0188] “Acylalkyl” is acylalkyl consisting of the above C₁-C₈ alkyl and the above C₂-C₁₄ acyl, and includes, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyrylmethyl, valerylmethyl, pivaloylmethyl, 2-acetylethyl, 2-propionylethyl, 3-acetylpropyl and the like.

[0189] “Cycloalkyl” means a cyclic (hydro)carbon chain of 3 to 8 carbon atoms. Cycloalkyl concretely includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with a preference for cycloalkyl having 3 to 6 carbon atoms. The cycloalkyl may have 1 to 5 substituent(s) and substitution sites are not particularly limited.

[0190] “Halogen” represents fluorine, chlorine, bromine or iodine.

[0191] “Amino” is primary amino, secondary or tertiary amino having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, amino, mono- or di-C₁-C₈ alkyl-substituted amino such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino and the like, with a preference for tertiary amino containing alkyl having 1 to 4 carbon atom(s).

[0192] “Alkylthio” is a linear or branched alkylthio having 1 to 6 carbon atom(s), and includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio (i.e., amylthio), hexylthio and structural isomers thereof, such as isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-pentylthio and the like, with a preference for alkylthio having 1 to 3 carbon atom(s).

[0193] “Phenylthio” means phenylthio optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0194] “Haloalkyl” is the above alkyl (e.g., C₁-C₈ alkyl) substituted by 1 to 5 halogen(s), and represents fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like.

[0195] “Aminoalkyl” is the above-mentioned alkyl (e.g., C₁-C₈ alkyl) having the above amino, preferably primary amino, and includes, for example, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2-diethylaminoethyl and the like, with a preference for aminoalkyl containing alkyl having 1 to 4 carbon atom(s), and aminoalkyl containing alkyl having 1 to 4 carbon atom(s) having tertiary amino.

[0196] “Acylamino” is acylamino having the above acyl (e.g., C₂-C₁₄ acyl), and represents, for example, acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino and the like.

[0197] “Alkoxy” is alkoxy having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy (i.e., amyloxy), hexyloxy and structural isomers thereof, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy and the like, with a preference for alkoxy having 1 to 4 carbon atom(s).

[0198] “Cycloalkoxy” is (cyclo)alkoxy having the above cycloalkyl (e.g., C₃-C₈ cycloalkyl), and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, with a preference for cycloalkoxy having cycloalkyl having 3 to 6 carbon atoms.

[0199] “Phenoxy” means phenyloxy optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0200] “Phenylalkoxy” is phenylalkoxy having the above alkoxy (e.g., C₁-C₈ alkoxy), and includes, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-methyl-1-phenylethoxy, 1-methyl-2-phenylethoxy, 1-phenylpropoxy, 2-pheylpropoxy, 1-methyl-1-phenylpropoxy, 1-methyl-2-phenylpropoxy, 1-methyl-3-phenylpropoxy and the like, with a preference for phenylalkoxy containing alkoxy having 1 to 4 carbon atom(s)

[0201] The phenylalkoxy optionally has 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0202] “Aminoalkoxy” is aminoalkoxy consisting of the above alkoxy (e.g., C₁-C₈ alkoxy) and amino, and includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, 4-(dimethylamino)butoxy and the like, with a preference for aminoalkoxy consisting of tertiary amino containing alkyl having 1 to 4 carbon atom(s), and alkoxy having 1 to 4 carbon atom(s).

[0203] “Alkoxyalkyl” is alkoxyalkyl consisting of the above alkoxy (e.g., C₁-C₈ alkoxy) and alkyl (e.g., C₁-C₈ alkyl), and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s).

[0204] “Phenoxyalkyl” is phenoxyalkyl containing of the above phenoxy and alkyl (e.g., C₁-C₈ alkyl), and includes, for example, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl and the like, with a preference for phenoxyalkyl containing alkyl having 1 to 4 carbon atom(s). The phenoxyalkyl optionally has 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0205] “Dialkoxyalkyl” is dialkoxyalkyl consisting of the above alkyl and alkoxy, and includes, for example, dimethoxymethyl, diethoxymethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl and the like, with a preference for dialkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s).

[0206] “Hydroxyalkyl” is hydroxyalkyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like, with a preference for hydroxyalkyl containing alkyl having 1 to 4 carbon atom(s).

[0207] “Alkoxycarbonyl” is alkoxycarbonyl having the above alkoxy (e.g., C₁-C₈ alkoxy), and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s). However, the alkoxycarbonyl of R⁴ is preferably alkoxycarbonyl having 2 to 5 carbon atoms.

[0208] “Phenoxycarbonyl” is phenoxycarbonyl optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0209] “Aminocarbonyl” is aminocarbonyl having the above amino (including mono- or di-C₁-C₈ alkyl-substituted amino), and includes, for example, aminocarbonyl (i.e., carbamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl, phenylcarbamoyl, benzylcarbamoyl and the like, with a preference for tertiary-aminocarbonyl containing alkyl having 1 to 4 carbon atom(s).

[0210] “Alkylthiocarbonyl” is alkylthiocarbonyl having the above alkylthio (e.g., C₁-C₆ alkylthio), and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec-butylthiocarbonyl, tert-butylthiocarbonyl and the like, with a preference for alkylthiocarbonyl, in which the alkyl moiety has 1 to 3 carbon atoms.

[0211] “Carboxyalkyl” is carboxyalkyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s).

[0212] “Cycloalkoxyalkyl” is cycloalkoxyalkyl having the above cycloalkoxy and alkyl (e.g., cycloalkoxyalkyl consisting of the above C₃-C₈ cycloalkoxy and C₁-C₈ alkyl), and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl and the like, with a preference for cycloalkoxyalkyl consisting of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atom(s). The cycloalkoxyalkyl optionally has 1 to 3 substituent(s) on the cycloalkyl and substitution sites are not particularly limited.

[0213] “Alkylsulfinyl” is alkylsulfinyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 5, preferably 1 to 4 carbon atom(s). The alkylsulfinyl of R⁴ is preferably alkylsulfinyl having 1 to 4 carbon atoms.

[0214] “Phenylsulfinyl” means phenylsulfinyl optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0215] “Alkylsulfonyl” is alkylsulfonyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl having 1 to 5, preferably 1 to 4 carbon atom(s). The alkylsulfonyl of R⁴ is preferably alkylsulfonyl having 1 to 4 carbon atoms.

[0216] “Phenylsulfonyl” means phenylsulfonyl optionally having 1 to 5 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0217] “Mercaptoalkyl” is mercaptoalkyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s).

[0218] “Alkylthioalkyl” is alkylthioalkyl having the above alkylthio and alkyl (e.g., alkylthioalkyl consisting of the above C₁-C₆ alkylthio and C₁-C₈ alkyl), and includes, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) and alkyl having 1 to 4 carbon atom(s).

[0219] “Aryl” is aryl having 6 to 14 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and the like. They may have 1 to 5 substituent(s) and substitution sites are not particularly limited.

[0220] “Aralkyl” is aralkyl wherein the above alkyl (e.g., C₁-C₈ alkyl) is substituted by the above aryl (e.g., C₆-C₁₄ aryl), and includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. These may have 1 to 5 substituent(s) on the aryl moiety and substitution sites are not particularly limited.

[0221] “Acyloxyacetyl” is acyloxyacetyl having the above acyl (e.g., C₂-C₁₄ acyl), and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.

[0222] “Acyloxyalkyl” is acyloxyalkyl having the above acyl (e.g., C₂-C₁₄ acyl) and alkyl (e.g., C₁-C₈ alkyl), and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-benzoyloxyethyl and the like.

[0223] The substituent of the “phenyl optionally having substituent(s)” is exemplified by those mentioned for the “substituent” below, wherein the number of the substituent is generally 1 to 5, preferably 1 to 3, more preferably 3. Phenyl having 1 or 2 substituent(s) is particularly preferable and substitution sites are not particularly limited.

[0224] “Aromatic heterocyclic group” is, for example, a 5- or 6-membered aromatic heterocyclic group optionally containing 1 to 3 heteroatom(s) selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and includes, for example, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, etc.), and the like. The aromatic heterocyclic group may have 1 to 6 substituent(s) and substitution sites are not particularly limited.

[0225] “Saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s)” includes the following groups and the like.

[0226] wherein R⁹ is each independently hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), or phenylalkyl optionally having substituent(s).

[0227] “Saturated 3 to 7 membered carbocyclic ring having substituent(s)” includes the following groups and the like.

[0228] wherein R¹⁰ is alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), or phenylalkyl optionally having substituent(s), and R^(10′) is hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), or phenylalkyl optionally having substituent(s).

[0229] The substituent of the “aromatic heterocyclic group optionally having substituent(s)” is exemplified by those mentioned for the “substituent” below, wherein the number of the substituent is generally 1 to 6, preferably 1 to 5, more preferably 3, and substitution sites are not particularly limited.

[0230] “Phenylalkyl” is phenylalkyl having the above alkyl (e.g., phenylalkyl consisting of phenyl and the above C₁-C₈ alkyl), and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 1-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s).

[0231] The kind and the number of the substituent of the “phenylalkyl optionally having substituent(s)” are the same as those for the above-mentioned “aromatic heterocyclic group” and substitution sites are not particularly limited.

[0232] “Alkoxycarbonylalkyl” is alkoxycarbonylalkyl having the above alkoxycarbonyl and alkyl, and includes, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl and the like.

[0233] “Alkoxycarbonylethenyl” is alkoxycarbonylethenyl having the above alkoxycarbonyl, and includes, for example, 2-methoxycarbonylethenyl, 2-ethoxycarbonylethenyl, 2-butoxycarbonylethenyl, 2-tert-butoxycarbonylethenyl and the like.

[0234] “Dialkylphosphinyl” is dialkylphosphinyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl and the like, with a preference for dialkylphosphinyl containing alkyl having 1 to 4 carbon atom(s).

[0235] “Dialkylphosphonyl” is dialkylphosphonyl having the above alkyl (e.g., C₁-C₈ alkyl), and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).

[0236] In the present specification, “substituent” includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic group, phenylalkyl, hydroxy, carboxy, thiol, halogen, amino, formyl, carbamoyl, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl and the like.

[0237] “Ring optionally containing heteroatom(s)” is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom(s) selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, with particular preference given to a ring containing sulfur atom. The ring may be substituted by one or more of the above substituents or oxo groups. The substitution site is not particularly limited. This ring is formed by R² and R³ in the formula (I) together with the attached carbon atom. By forming this ring, a spiro ring is formed in the compound of the formula (I). The above ring can be fused with a benzene ring optionally having substituent(s) and substitution sites are not particularly limited. Such a ring includes, for example, 2,3-dihydrobenzo[b]thiophene, 2,3-dihydrobenzo[b]thiophen-1-oxide and the like.

[0238] “A group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring” represents a group derived from naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indan and the like, with preference given to naphthalene (namely naphthyl) and particular preference given to 1-naphthyl. Of these, naphthyl such as naphthalen-1-yl and the like, and indanyl such as indan-4-yl and the like are preferable. The group may have 1 to 4 substituent(s) and substitution sites are not particularly limited.

[0239] “A group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s)” includes the following groups and the like.

[0240] Of these, 2,1,3-benzoxadiazole, dihydrobenzo [b] furan, methylenedioxyphenyl and 3,4-dihydro-2H-benzopyrane are preferable, and 2,1,3-benzoxadiazol-4-yl, 2,3-dihydrobenzo-[b]furan-7-yl, 2,3-(methylenedioxy)phenyl and 3,4-dihydro-2H-benzopyran-8-yl are particularly preferable. The group may have 1 to 3 substituent(s) and substitution sites are not particularly limited.

[0241] Of these, 2,1,3-benzoxadiazole and 3,4-dihydro-2H-benzopyrane are preferable, and 2,1,3-benzoxadiazol-4-yl and 3,4-dihydro-2H-benzopyran-8-yl are particularly preferable.

[0242] “A group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring” includes the following groups and the like.

[0243] The group may have 1 to 5 substituent(s) and substitution sites are not particularly limited.

[0244] “Alkylcarbonylalkyl” is, for example, C₁-C₄ alkyl-carbonyl-C₁-C₄ alkyl, and includes, for example, methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butylcarbonylmethyl and the like.

[0245] “Arylaminocarbonyl” is C₆-C₁₀ aryl-aminocarbonyl, and includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl and the like. The arylaminocarbonyl optionally has 1 to 3 substituent(s) on the aryl and substitution sites are not particularly limited.

[0246] “Aralkylaminocarbonyl” is C₇-C₁₄ aralkyl-aminocarbonyl, and includes, for example, benzylaminocarbonyl and the like. The aralkylaminocarbonyl optionally has 1 to 3 substituent(s) on the aryl and substitution sites are not particularly limited.

[0247] “Alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent” means C₁-C₈ alkyl substituted by “a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s)”, such as pyrrole, pyrroline, pyrazole, pyridine, piperidine, piperazine, homopiperadine or morpholine and the like, which optionally has a substituent such as C₁-C₄ alkyl, C₆-C₁₀ aryl such as phenyl, naphthyl and the like, and includes, for example, (4-phenylpiperazin-1-yl)methyl, 2-(4-phenylpiperazin-1-yl)ethyl, 3-(4-phenylpiperazin-1-yl)propyl, (4-(naphthalen-1-yl)piperazin-1-yl)methyl, 2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl, (4-methylhomopiperazin-1-yl)methyl and the like.

[0248] “Phenylaminoalkyl” is phenylamino-C₁-C₄ alkyl, and includes, for example, phenylaminomethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl and the like. The phenylaminoalkyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0249] “Phenylalkylcarbonyl” is phenyl-C₁-C₄ alkyl-carbonyl, and includes, for example, benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl and the like. The phenylalkylcarbonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0250] “Alkyl” in the R¹¹ is C₁-C₄ alkyl, and includes, for examples, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl and the like.

[0251] “Alkylsulfonyl” in the R¹¹ is C₁-C₄ alkyl-sulfonyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.

[0252] “Phenylsulfonyl” in the R¹¹ is phenylsulfonyl optionally having 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0253] “Phenylalkylsulfonyl” in the R¹¹ is phenyl-C₁-C₄ alkyl-sulfonyl, and includes, for example, benzylsulfonyl, 2-phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl and the like. The phenylalkylsulfonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0254] “Alkylsulfinyl” in the R¹¹ is C₁-C₄ alkyl-sulfinyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.

[0255] “Phenylsulfinyl” in the R¹¹ is phenylsulfinyl optionally having 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0256] “Phenylalkylsulfinyl” in the R¹¹ is phenyl-C₁-C₄ alkyl-sulfinyl, and includes, for example, benzylsulfinyl, 2-phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4-phenylbutylsulfinyl and the like. The phenylalkylsulfinyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0257] “Alkoxycarbonyl” in the R¹¹ is C₁-C₄ alkoxy-carbonyl, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.

[0258] “Phenylalkoxycarbonyl” in the R¹¹ is phenyl-C₁-C₄ alkoxy-carbonyl, and includes, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl and the like. The phenylalkoxycarbonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0259] “Alkylcarbonyl” in the R¹¹ is C₁-C₄ alkyl-carbonyl and includes, for example, acetyl, propionyl, butylcarbonyl and the like.

[0260] “Phenylcarbonyl” in the R¹¹ is phenylcarbonyl optionally having 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0261] “Phenylalkylcarbonyl” in the R¹¹ is phenyl-C₁-C₄ alkyl-carbonyl, and includes, for example, benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4-phenylbutylcarbonyl and the like. The phenylalkylcarbonyl optionally has 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0262] “Phenoxycarbonyl” in the R¹¹ means phenoxycarbonyl optionally having 1 to 3 substituent(s) on the phenyl and substitution sites are not particularly limited.

[0263] “Alkyl” in the R¹² is C₁-C₄ alkyl, and includes, for examples, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl and the like.

[0264] The “5 or 6-membered ring optionally containing heteroatom(s)” is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom(s) consisting of nitrogen atom, oxygen atom and sulfur atom. Examples thereof include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, pyrroline, pyrrolidine, imidazoline and imidazolidine. Of these, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan and pyridine are preferable.

[0265] The compounds represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention. Such acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like. Furthermore, the compounds of the present invention can form hydrates, solvates with ethanol and the like, and crystal polymorphs. When an asymmetric carbon atom exists, optical isomers and racemates thereof can be present, and all of these are encompassed in the present invention.

[0266] Of the compounds (I) of the present invention, a compound wherein R⁰ is hydrogen can be synthesized as shown in the following according to the method described in J. Chem. Soc., Perkin Trans. 1, 947 (1996) and the like.

[0267] First Production Method

[0268] wherein R², R³, R⁴ and R⁵ are as defined above.

[0269] Meldrum's acid of the formula (VI) and a carbonyl derivative of the formula (VII) are reacted with a carbonyl derivative of the formula (VIII), if desired, in the presence of ammonium acetate, to give an amide derivative of the formula (IX). The reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction. As the solvent, formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used. The reaction is carried out at any temperature, for example, from 0° C. to 200° C., preferably from 60° C. to 100° C.

[0270] wherein R², R³, R⁴ and R⁵ are as defined above.

[0271] The obtained amide derivative of the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of the formula (X). The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide and the like are generally used. The reaction is carried out at any temperature, for example, from 0° C. to 200° C., preferably from 0° C. to 100° C., more preferably from 0° C. to 60° C. or 60° C. to 100° C.

[0272] wherein R¹ (e.g., hydrogen), R², R³, R⁴ and R⁵ are as defined above.

[0273] The compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, alcohol and the like are generally used. The reaction is carried out at any temperature, for example, from 0° C. to 200° C., preferably from 60° C. to 100° C.

[0274] The carbonyl derivative of the formula (VII), which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983). The carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993).

[0275] Second Production Method

[0276] wherein R¹, R², R³, R⁴ and R⁵ are as defined above.

[0277] The compounds (I) of the present invention can be produced by reacting aminopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII). The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used. The reaction is carried out at any temperature, for example, from 0° C. to 200° C., preferably from 60° C. to 100° C.

[0278] Of the compounds (I) of the present invention, a compound wherein R⁰ is a substituent other than hydrogen can be synthesized as follows.

[0279] Third Production Method

[0280] wherein R⁰, R¹, R², R³, R⁴ and R⁵ are as defined above, and X represents halogen, provided that R⁰ is not hydrogen.

[0281] The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with halide of the formula (XII) in the presence of a base. Suitable base includes, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like. The reaction is carried out at any temperature, for example, from −10° C. to 200° C., preferably from 0° C. to 100° C.

[0282] Fourth Production Method

[0283] wherein R⁰, R¹, R², R³, R⁴ and R⁵ are as defined above, provided that R⁰ is not hydrogen.

[0284] The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) such as acetic anhydride or the like in the presence of a base. Suitable base includes, for example, triethylamine, pyridine, 4-dimethylaminopyridine and the like. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like. The reaction is carried out at any temperature, for example, from −10° C. to 200° C., preferably from 0° C. to 100° C.

[0285] Those skilled in the art should understand that the above production methods can be modified corresponding to the desired compounds.

[0286] The compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation and purification is carried out by a conventional chemical process such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography and the like. When the purified product thus obtained is a racemate, a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column packed with optically active carrier. The present invention also encompasses optically active compounds.

[0287] The compounds of the present invention obtained by the above methods have a weak inhibitory activity on kinases other than GSK-3β such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3β. Therefore, the compounds of the present invention have a GSK-3β-selective inhibitory activity and can be medicaments with small side-effect for diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic-depressive psychosis and the like), alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors. In addition, the compounds of the present invention are useful as immunopotentiators.

[0288] Formulations comprising the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives conventionally used for formulation. The carrier and excipient for formulation may be a solid or liquid, and include, for example, lactose, magnesium stearate, starch such as corn starch and the like, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene glycol and other conventionally used substances. Administration may be oral administration of tablet, pill, capsule, granule, powder, solution and the like, or parenteral administration by injection (intravenous injection, intramuscular injection and the like), suppository, transdermal agent and the like. While the dose is appropriately determined on each case in consideration of symptom, age and sex of the administration subject, and the like, it is generally 1-1,000 mg, preferably 50-200 mg per day for an adult person, which is orally administered once to several times a day, or 1-500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day.

[0289] As solid compositions for oral administration according to the present invention, tablet, powder, granule and the like are used. In such a solid composition, one or more active substances are mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid and magnesium aluminate. The composition may contain, according to a conventional method, inert additives other than diluent, for example, a lubricant such as magnesium stearate, a disintegrator such as cellulose and calcium glycolate, a stabilizer such as lactose and a solubilizer such as glutamic acid and aspartic acid. Tablet and pill may be coated with a gastric or enteric coating film of, for example, sucrose, gelatin, hydroxypropylcellulose and the like. Liquid compositions for oral administration include pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like, and contain an inert diluent generally used, such as purified water and ethanol. This composition may contain an adjuvant such as wetting agent and suspending agent, a sweetener, a flavor, an aromatic and an antiseptic, in addition to the inert diluent. Injections for parenteral administration contain sterile aqueous or non-aqueous solution, suspension and emulsion. The aqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such a composition may contain adjuvants such as antiseptic, wetting agent, emulsifier, dispersant, stabilizer and solubilizer. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of an antimicrobial agent, irradiation of ultraviolet ray and the like. Alternatively, a sterile solid composition may be prepared and used upon dissolution in sterile water or sterile solvent for injection prior to use.

EXAMPLE

[0290] The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples.

Example 1 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0291] A solution of 2-chlorobenzaldehyde (1.7 g), 3-aminopyrazole (1.0 g) and ethyl acetoacetate (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give the title compound (850 mg) as colorless crystals.

[0292] Melting Point (MP): 217-221° C.

[0293] Anal. Calcd. for: C₁₆H₁₆N₃O₂Cl: C,60.47;H,5.08;N,13.22.

[0294] Found: C,60.15;H,5.07;N,13.53.

[0295] MS(EI): 317(M+).

[0296]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.00(3H,t,J=6.8 Hz), 2.25(3H,s), 3.72-3.82(2H,m), 5.57(1H,s), 7.07-7.12(2H,m), 7.18(1H,d,J=7.3 Hz), 7.26(1H,s), 7.34(1H,d,J=7.9 Hz), 9.53(1H,br.s), 11.98(1H,br.s).

[0297] IR(KBr): ν=3393,3267,1670,1589,1518,1278,1217 cm⁻¹.

Example 2 Ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0298] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.

[0299] MP: 196-200° C.

[0300] Anal. Calcd. for: C₁₇H₁₉N₃O 1/5 H₂O:C,64.42;H,6.17;N,13.26.

[0301] Found: C,64.08;H,6.05;N,13.68.

[0302] MS(EI): 313(M⁺).

[0303]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.00 (3H,t,J=6.8 Hz), 2.81(3H,s), 3.72(3H,s), 3.87(2H,q,J=6.8 Hz), 5.54(1H,s), 6.80(1H,dd,J=7.3 Hz and 7.4 Hz), 6.90(1H,d,J=7.8 Hz), 7.04(1H,d,J=7.4 Hz), 7.13-7.15(2H,m), 9.99(1H,br.s), 11.98(1H,br.s).

[0304] IR(KBr): ν=3362,3267,3204,3090,1662,1589,1516,1275,1097 cm⁻¹.

Example 3 Ethyl 4,7-dihydro-6-methyl-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0305] The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.

[0306] MP: 259-262° C.

[0307] Anal. Calcd. for: C₁₇H₁₆F₃N₃O₂ 1/5 H₂O:C,57.53;H,4.66;N,11.84.

[0308] Found: C,57.56;H,4.68;N,11.86.

[0309] MS(EI): 352(M⁺+1).

[0310]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.74 (3H,t,J=6.9 Hz), 2.40(3H,s), 3.68-3.81(2H,m), 5.42(1H,s), 7.00(1H,s), 7.28(1H,dd,J=7.3 Hz and 7.4 Hz), 7.33(1H,d,J=7.2 Hz), 7.51(1H,dd,J=7.3 Hz and 7.4 Hz), 7.60(1H,d,J=7.8 Hz), 9.58(1H,br.s), 12.00(1H,br.s).

[0311] IR(KBr): ν=3277,3209,3094,1668,1593,1514,1313,1213,1153,1097, 765 cm³¹ ¹.

Example 4 Methyl 4-(2-chlorophenyl)-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0312] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl acetoacetate in the same manner as in Example 1.

[0313] MP: 235° C.

[0314] Anal. Calcd. for: C₁₅H₁₄ClN₃O₂ 2/5 H₂O:C,57.94;H,4.80;N,13.51.

[0315] Found: C,58.03;H,4.55;N,13.43.

[0316] MS(EI): 303(M⁺).

[0317]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.40(3H,s), 3.34(3H,s), 5.55(1H,s), 7.09-7.11(2H,m), 7.18(1H,dd,J=7.3 Hz and 7.4 Hz), 7.29(1H,s), 7.34(1H,d,J=7.3 Hz), 9.57(1H,br.s), 12.00(1H,br.s).

Example 5

[0318] t-Butyl 4-(2-chlorophenyl)-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0319] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and t-butyl acetoacetate in the same manner as in Example 1.

[0320] MP: 207° C.

[0321] Anal. Calcd. for: C₁₈H₂₀ClN₃O₂:C,62.52;H,5.83;N,12.15.

[0322] Found: C,62.51;H,5.79;N,12.17.

[0323] MS(EI): 345(M⁺).

[0324]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.07(9H,s), 2.36(3H,s), 5.50(1H,s), 7.11-7.15(2H,m), 7.20(1H,d,J=7.3 Hz), 7.25(1H,s), 7.37(1H,d,J=7.3 Hz), 9.35(1H,br.s), 11.93(1H,br.s).

Example 6 Isopropyl 4-(2-fluorophenyl)-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0325] The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and isopropyl acetoacetate in the same manner as in Example 1.

[0326] MP: 218-220° C.

[0327]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.66(3H,d,J=6.3 Hz), 1.02(3H,d,J=6.3 Hz), 2.37(3H,s), 4.66(1H,q,J=6.3 Hz), 5.40(1H,s), 7.01-7.14(4H,m), 7.19(1H,s), 9.46(1H,br.s), 11.97(1H,br.s).

Example 7 Benzyl 4-(2-chlorophenyl)-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0328] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and benzyl acetoacetate in the same manner as in Example 1.

[0329] MP: 234° C.

[0330] Anal. Calcd. for: C₂₁H₁₈ClN₃O₂:C,66.40;H,4.78;N,11.06.

[0331] Found: C,66.16;H,4.86;N,10.92.

[0332] MS(EI): 379(M⁺).

[0333]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.43(3H,s), 4.81(1H,d,J=12.6 Hz), 4.92(1H,d,J=12.6 Hz), 5.62(1H,s), 6.86-6.88(2H,m), 7.13-7.18(6H,m), 7.31-7.34(2H,m), 9.65(1H,br.s), 12.01(1H,br.s).

Example 8 4-(2-Chlorophenyl)-5-dimethylaminocarbonyl-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine

[0334] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and N,N-dimethylacetamide in the same manner as in Example 1.

[0335] MP: 229° C.

[0336] Anal. Calcd. for: C₁₆H₁₇ClN₄O 1/2 H₂O:C,58.99;H,5.57;N,17.20.

[0337] Found: C,58.90;H,5.46;N,16.84.

[0338] MS(EI): 316(M⁺).

[0339]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.77(3H,s), 2.72(6H,s), 5.39(1H,s), 7.10-7.22(4H,m), 7.30(1H,d,J=7.3 Hz), 8.40(1H,br.s), 11.83(1H,br.s).

Example 9 4-(2-Chlorophenyl)-5-hydrazinocarbonyl-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine

[0340] To a solution of 4-(2-chlorophenyl)-4,7-dihydro-5-dimethylaminocarbonyl-6-methyl-2H-pyrazolo[3,4-b]pyridine (200 mg) in acetonitrile (200 mL) was added hydrazine (200 mg) and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound as colorless crystals (150 mg).

[0341] MP: 220° C.

[0342] Anal. Calcd. for: C₁₄H₁₄ClN₅O 3/10 H₂O:C,54.39;H,4.76;N,22.65.

[0343] Found: C,54.36;H,4.56;N,22.65.

[0344] MS(EI): 303(M⁺).

[0345]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.85(3H,s), 3.20-3.80(3H,br.s), 5.15(1H,s), 6.81(1H,s), 7.16-7.028(3H,m), 7.34(1H,d,J=7.3 Hz), 10.05-11.07(2H,brs).

Example 10 4-(2-Fluorophenyl)-4,7-dihydro-6-methyl-5-isopropylthiocarbonyl-2H-pyrazolo[3,4-b]pyridine

[0346] The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and acetoacetic acid isopropyl thioester in the same manner as in Example 1.

[0347] MP: 192-194° C.

[0348]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.03(3H,d,J=6.9 Hz), 1.15(3H,d,J=6.9 Hz), 2.43(3H,s), 3.35(1H,q,J=6.9 Hz), 5.55(1H,s), 7.04-7.15(4H,m), 7.33(1H,s), 9.81(1H,br.s), 12.11(1H,br.s).

Example 11 4,7-Dihydro-6-methyl-5-nitro-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine

[0349] The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and 1-nitropropan-2-one in the same manner as in Example 1.

[0350] MP: 257-258° C.

[0351]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.65(3H,s), 5.75(1H,s), 7.19(1H,s), 7.30-7.35(2H,m), 7.51(1H,dd,J=7.3 Hz and 7.8 Hz), 7.66(1H,d,J=7.8 Hz), 10.87(1H,br.s), 12.45(1H,br.s).

Example 12 Ethyl 4,7-dihydro-4-phenyl-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0352] The title compound was prepared from benzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0353] MP: 110-115° C.

[0354] Anal. Calcd. for: C₁₆H₁₄N₃O₂F₃ 1/2 H₂O:C,55.49;H,4.37;N,12.13.

[0355] Found: C,55.84;H,4.70;N,11.89.

[0356] MS(EI): 337(M⁺).

[0357]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=6.9 Hz), 3.90(2H,q,J=6.8 Hz), 5.54(1H,s), 7.13-7.17(3H,m), 7.24-7.28(3H,m), 9.78(1H,br.s), 12.20(1H,br.s).

[0358] IR(KBr): ν=3375,3175,3067,1707,1606,1533,1278,1206,1197,1167 cm⁻¹.

Example 13 Ethyl 4-(2-fluorophenyl)-4,7-dihydro-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0359] The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0360] MP: 119-120° C.

[0361] Anal. Calcd. for: C₁₆H₁₃F₄N₃O₂:C,54.09;H,3.69;N,11.84.

[0362] Found: C,53.84;H,3.57;N,11.79.

[0363] MS(EI): 356(M⁺+1).

[0364]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94 (3H,t,J=6.8 Hz), 3.89(2H,q,J=6.8 Hz), 5.46(1H,s), 7.11-7.20(4H,m), 7.28-7.30(1H,m), 9.92(1H,br.s), .12.27(1H,br.s).

[0365] IR(KBr): ν=3290,3178,3069,1703,1608,1537,1280,1232,1174,1138, 756 cm⁻¹.

Example 14 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0366] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0367] MP: 171-172° C.

[0368] MS(EI): 371(M⁺).

[0369]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91 (3H,t,J=7.3 Hz), 3.50(3H,br.s), 3.87 (2H,q,J=6.8 Hz), 5.66(1H,s), 6.26(2H,s), 7.15-7.18(2H,m), 7.27(1H,d,J=7.8 Hz), 7.30(1H,s), 7.40(1H,d,J=7.8 Hz), 9.65(1H,br.s).

[0370] IR(KBr): ν=3297,2935,1730,1624,1550,1479,1186 cm⁻¹.

Example 15 Ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0371] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0372] MP: 144-146° C.

[0373] Anal. Calcd. for: C₁₇H₁₆F₃N₃O₃:C,55.59;H,4.39;N,11.44.

[0374] Found: C,55.55;H,4.38;N,11.43.

[0375] MS(EI): 367(M⁺).

[0376]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=6.8 Hz), 3.83(3H,s), 3.89(2H,q,J=6.8 Hz), 5.51(1H,s), 6.84(1H,dd,J=7.3 Hz and 7.4 Hz), 6.94-6.97(2H,m), 7.13(1H,dd,J=7.3 Hz and 7.4 Hz), 7.20(1H,s), 9.70(1H,br.s), 12.13(1H,br.s).

[0377] IR(KBr): ν=3431,3173,3067,2993,2924,1689,1610,1527,1286,1226, 1145 cm⁻¹.

Example 16 Ethyl 4,7-dihydro-6-trifluoromethyl-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0378] The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0379] MP: 182-186° C.

[0380] Anal. Calcd. for: C₁₇H₁₃N₃O₂F₆:C,50.38;H,3.23;N,10.37.

[0381] Found: C,50.21;H,3.15;N,10.39.

[0382] MS (FAB): 406(M⁺+1).

[0383]¹-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83 (3H,t,J=6.8 Hz), 3.83(2H,q,J=6.8 Hz), 5.49(1H,s), 7.08(1H,s), 7.35-7.39(2H,m), 7.62(1H,dd,J=7.3 Hz and 7.4 Hz), 7.66(1H,d,J=7.8 Hz), 9.97(1H,br.s), 12.30(1H,br.s).

[0384] IR(KBr): ν=3339,3177,3067,1711,1608,1537,1313,1280,1182,1141 cm⁻¹.

Example 17 Ethyl 4-(3-chlorophenyl)-4,7-dihydro-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0385] The title compound was prepared from 3-chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0386] MP: 144-145° C.

[0387] Anal. Calcd. for: C₁₆H₁₃N₃O₂F₃Cl: C,51.69;H,3.52;N,11.30.

[0388] Found: C,51.33;H,3.74;N,11.10.

[0389] MS(EI): 371(M⁺).

[0390]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.98 (3H,t,J=6.8 Hz), 3.92(2H,q,J=6.8 Hz), 5.21(1H,s), 7.11(1H,d,J=7.8 Hz), 7.17(1H,s), 7.23(1H,d,J=8.7 Hz), 7.29-7.33(2H,m), 9.92(1H,br.s), 12.30(1H,br.s).

[0391] IR(KBr): ν=3321,3178,3070,1703,1610,1535,1278,1224,1184,1145 cm⁻¹.

Example 18 Ethyl 4-(4-chlorophenyl)-4,7-dihydro-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0392] The title compound was prepared from 4-chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0393] MP: 176-178° C.

[0394] Anal. Calcd. for: C₁₆H₁₃F₃N₃O₂Cl: C,51.69;H,3.52;N,11.30.

[0395] Found: C,51.91;H,3.77;N,11.08.

[0396] MS(EI): 371(M⁺).

[0397]¹H-NMR (400 MHZ,DMSO-d₆)δ(ppm): 0.98 (3H,t,J=6.8 Hz), 3.90(2H,q,J=7.3 Hz), 5.92(1H,s), 7.16(2H,d,J=8.2 Hz), 7.27(1H,s), 7.31(2H,d,J=8.2 Hz), 9.87(1H,br.s), 12.27(1H,br.s).

[0398] IR(KBr): ν=3476,3368,3178,3078,1714,1695,1606,1537,1278,1172, 1134 cm³¹ ¹.

Example 19 Ethyl 4,7-dihydro-4-(4-methoxyphenyl)-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0399] The title compound was prepared from 4-methoxybenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0400] MP: 159-161° C.

[0401] Anal. Calcd. for: C₁₇H₁₆FN₃O₃:C,55.59;H,4.39;N,11.44.

[0402] Found: C,55.49;H,4.54;N,11.33.

[0403] MS(EI): 367(M⁺).

[0404]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.99 (3H,t,J=7.3 Hz), 3.68(3H,s), 3.89(2H,q,J=7.3 Hz), 5.12(1H,s), 6.82(2H,d,J=8.7 Hz), 7.03(2H,d,J=8.7 Hz), 7.22-7.24(1H,m), 9.71(1H,br.s), 12.19(1H,br.s).

[0405] IR(KBr): ν=3323,3231,3173,3067,1699,1610,1535,1510,1302,1248,1184,1145 cm⁻¹.

Example 20 Ethyl 4-(4-ethoxycarbonylphenyl)-4,7-dihydro-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0406] The title compound was prepared from 4-ethoxycarbonylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0407] MP: 157-160° C.

[0408] Anal. Calcd. for: C₁₉H₁₈F₃N₃O₄:C,55.75;H,4.43;N,10.26.

[0409] Found: C,55.68;H,4.39;N,10.43.

[0410] MS (FAB): 410(M⁺+1).

[0411]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.96 (3H,t,J=6.9 Hz), 1.28 (3H,t,J=7.3 Hz), 3.89(2H,q,J=6.8 Hz), 4.27(2H,q,J=7.3 Hz), 5.28(1H,s), 7.27(1H,s), 7.29(2H,d,J=8.3 Hz), 7.87(2H,d,J=8.2 Hz), 9.92(1H,br.s), 12.28(1H,br.s).

[0412] IR(KBr): ν=3393,3188,3082,1692,1612,1539,1284 cm⁻¹.

Example 21 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-3-methyl-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0413] The title compound was prepared from 2-chlorobenzaldehyde, 3-amino-5-methylpyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0414] MP: 165-168° C.

[0415] MS(EI): 385(M⁺).

[0416]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94 (3H,t,J=7.3 Hz), 1.81 (3H,s), 3.85(2H,q,J=6.8 Hz), 5.54(1H,s), 7.17-7.20(2H,m), 7.27(1H,dd,J=7.3 Hz and 7.4 Hz), 7.36(1H,d,J=8.3 Hz), 9.79(1H,br.s), 11.96(1H,br.s).

[0417] IR(KBr): ν=3263,3194,3080,1668,1591,1520,1286,1232,1149,1095, 1062 cm⁻¹.

Example 22 Ethyl 4,7-dihydro-4-(thiophen-2-yl)-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0418] The title compound was prepared from thiophene-2-aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0419] MP: 157-161° C.

[0420] Anal. Calcd. for: C₁₄H₁₂F₃N₃O₂S: C,49.27;H,2.95;N,12.31.

[0421] Found: C,49.10;H,3.28;N,12.13.

[0422] MS(EI): 343(M⁺).

[0423]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.08 (3H,t,J=7.4 Hz), 4.00 (2H,q,J=7.4 Hz), 5.52(1H,s), 6.76(1H,d,J=2.9 Hz), 6.87(1H,dd,J=2.9 Hz and 5.4 Hz), 7.30(1H,d,J=5.4 Hz), 7.43(1H,s), 9.96(1H,br.s), 12.35(1H,br.s).

[0424] IR(KBr): δ=3350,3240,3180,1693,1612,1535,1396,1371,1304,1153,1093,1057,694 cm⁻¹.

Example 23 Ethyl 4,7-dihydro-4-(thiophen-3-yl)-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0425] The title compound was prepared from thiophene-3-aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0426] MP: 140-145° C.

[0427] Anal. Calcd. for: Cl₄H₁₂F₃N₃O₂S: C,49.27;H,2.95;N,12.31.

[0428] Found: C,49.65;H,2.64;N,12.19.

[0429] MS(EI): 343(M⁺).

[0430]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.03 (3H,t,J=7.3 Hz), 3.96 (2H,q,J=7.3 Hz), 5.30(1H,s), 6.87(1H,d,J=4.8 Hz), 7.05(1H,s), 7.35(1H,s), 7.39(1H,dd,J=2.9 Hz and 4.8 Hz), 9.76(1H,br.s), 12.25(1H,br.s).

[0431] IR(KBr): ν=3356,3182,2982,2932,1689,1614,1537,1304,1224,1153 cm⁻¹.

Example 24 Ethyl 4,7-dihydro-4-(1-naphthyl)-6-trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0432] The title compound was prepared from naphthalene-1-aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.

[0433] MP: 119-120° C.

[0434] Anal. Calcd. for: C₂₀H₁₆F₃N₃O₂ 1/2 H₂O:C,60.45;H,4.57;N,10.57.

[0435] Found: C,60.20;H,4.77;N,10.39.

[0436] MS (FAB): 388(M⁺+1).

[0437]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.69 (3H,t,J=6.8 Hz), 3.73(2H,q,J=6.8 Hz), 6.04(1H,s), 7.09(1H,s), 7.26(1H,d,J=6.8 Hz), 7.41(1H,dd,J=7.3 Hz and 7.4 Hz), 7.52-7.58(2H,m), 7.75(1H,d,J=8.3 Hz), 7.92(1H,dd,J=7.3 Hz and 7.4 Hz), 8.33(1H,s), 9.87(1H,br.s), 12.14(1H,br.s).

[0438] IR(KBr): ν=3173,1670,1606,1138,1095 cm⁻¹.

Example 25 Ethyl 4,7-dihydro-4-phenyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0439] A solution of benzaldehyde (1.6 g), 3-aminopyrazole (1.0 g) and ethyl 3-ketohexanoate (1.9 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give the title compound (720 mg) as colorless crystals.

[0440] MP: 139-141° C.

[0441] Anal. Calcd. for: C₁₈H₂₁N₃O₂C₄H₄O₄ 1/2 H₂O:C,60.54;H,6.00;N,9.63.

[0442] Found: C,60.16;H,5.60;N,10.01.

[0443] MS(EI): 311(M⁺).

[0444]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94-0.95 (6H,m), 1.62 (2H,q,J=7.8 Hz), 2.66-2.77(2H,m), 3.50(3H,br.s), 3.83(2H,q,J=6.8 Hz), 5.10(1H,s), 6.25(2H,s), 7.05-7.20(6H,m), 9.37(1H,br.s).

[0445] IR(KBr): ν=3337,3042,1699,1593,1467,1539,1361,1203 cm⁻¹

Example 26 Ethyl 4-(2-fluorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0446] The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0447] MP: 192-194° C.

[0448] Anal. Calcd. for: C₁₈H₂₀FN₃O₂ 1/2 H₂O:C,63.89;H,6.26;N,12.42.

[0449] Found: C,63.85;H,6.01;N,12.36.

[0450] MS(EI): 329(M⁺).

[0451]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93 (3H,t,J=7.3 Hz), 0.97 (3H,t,J=7.3 Hz), 1.62-1.68(2H,m), 2.71-2.83(2H,m), 3.82(2H,q,J=7.3 Hz), 5.43(1H,s), 7.05-7.11(4H,m), 7.21(1H,s), 9.48(1H,br.s), 11.97(1H,br.s).

[0452] IR(KBr): ν=3265,3198,2964,1591,1514,1224,1209,1093 cm⁻¹.

Example 27 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0453] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0454] MP: 202-205° C.

[0455] Anal. Calcd. for: C₁₈H₂₀ClN₃O₂:C,62.52;H,5.83;N,12.15.

[0456] Found: C,62.28;H,5.76;N,12.37.

[0457] MS(FAB): 346(M⁺+1).

[0458]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85 (3H,t,J=6.8 Hz), 0.95 (3H,t,J=7.3 Hz), 1.62-1.68(2H,m), 2.67-2.87(2H,m), 3.78(2H,q,J=6.8 Hz), 5.58(1H,s), 7.07-7.11(2H,m), 7.18(1H,dd,J=7.3 Hz and 7.4 Hz), 7.25(1H,s), 7.34(1H,d,J=7.8 Hz), 9.49(1H,br.s), 11.97(1H,br.s).

[0459] IR(KBr): ν=3263,3209,3194,3080,1668,1591,1520,1286,1232,1149,1062,750 cm⁻.

Example 28 Methyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0460] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl 3-ketohexanoate in the same manner as in Example 25.

[0461] MP: 203-207° C.

[0462] Anal. Calcd. for: C₁₇H₁₈ClN₃O₂ 1/5 H₂O:C,60.88;H,5.53;N,12.53.

[0463] Found: C,60.73;H,5.36;N,12.14.

[0464] MS(EI): 331(M⁺).

[0465]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.97 (3H,t,J=7.3 Hz), 1.64-1.66(2H,m), 2.72-2.83(2H,m), 3.31(3H,s), 5.57(1H,s), 7.10(1H,d,J=7.3 Hz), 7.09-7.11(1H,m), 7.17-7.18(1H,m), 7.27(1H,s), 7.34(1H,d,J=7.8 Hz), 9.54(1H,br.s), 11.97(1H,br.s).

[0466] IR(KBr): ν=3260,3190,1672,1591,1516,1232 cm⁻¹.

Example 29 Ethyl 4-(2-bromophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0467] The title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0468] MP: 223° C.

[0469] Anal. Calcd. for: C₁₈H₂₀BrN₃O₂:C,55.40;H,5.17;N,10.77.

[0470] Found: C,55.08;H,5.14;N,10.85.

[0471] MS(EI): 390(M⁺).

[0472]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.63-1.69(2H,m), 2.71-2.74(1H,m), 2.80-2.83(1H,m), 3.77(2H,q,J=7.3 Hz), 5.67(1H,s), 7.00(1H,dd,J=7.3 Hz and 7.4 Hz), 7.10(1H,d,J=7.3 Hz), 7.22(1H,dd,J=7.3 Hz and 7.4 Hz), 7.28(1H,s), 7.51(1H,d,J=7.3 Hz), 9.50(1H,br.s), 11.97(1H,br.s).

Example 30 Ethyl 4,7-dihydro-4-(2-methylphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0473] The title compound was prepared from 2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0474] MP: 178° C.

[0475] Anal. Calcd. for: C₁₉H₂₃N₃O₂:C,70.13;H,7.12;N,12.91.

[0476] Found: C,70.12;H,7.35;N,12.99.

[0477] MS(EI): 325(M⁺).

[0478]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.62-1.66(2H,m), 2.44(3H,s), 2.64-2.66(1H,m), 2.76-2.79(1H,m), 3.77(2H,q,J=7.3 Hz), 5.31(1H,s), 6.93(1H,d,J=7.3 Hz), 6.99-7.05(3H,m), 7.18(1H,s), 9.34(1H,br.s), 11.87(1H,br.s).

Example 31 Ethyl 4,7-dihydro-6-propyl-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0479] The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0480] MP: 198-202° C.

[0481] Anal. Calcd. for: C₁₉H₂₀F₃N₃O₂ 1/2 H₂O:C,58.76;H,5.45;N,10.81.

[0482] Found: C,58.82;H,5.92;N,10.62.

[0483] MS(EI): 379(M⁺).

[0484]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.76 (3H,t,J=7.3 Hz), 0.98(3H,t,J=7.3 Hz), 1.64-1.68(2H,m), 2.76-2.79(2H,m), 3.80(2H,q,J=7.3 Hz), 5.44(1H,s), 7.00(1H,s), 7.27-7.30(1H,m), 7.33(1H,d,J=7.8 Hz), 7.53(1H,dd,J=7.3 Hz and 7.4 Hz), 7.61(1H,d,J=7.3 Hz), 9.54(1H,br.s), 11.99(1H,br.s).

[0485] IR(KBr): ν=3265,3198,2964,1591,1514,1224,1209,1093 cm⁻¹.

Example 32 Ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0486] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0487] MP: 169° C.

[0488] Anal. Calcd. for: C₁₉H₂₃N₃O₃:C,66.84;H,6.79;N,12.31.

[0489] Found: C,66.58;H,6.50;N,12.34.

[0490] MS(EI): 341(M⁺).

[0491]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.66-1.68(2H,m), 2.66-2.70(1H,m), 2.81-2.88(1H,m), 3.80(2H,q,J=7.3 Hz), 3.85(3H,s), 5.47(1H,s), 6.76(1H,dd,J=7.3 Hz and 7.4 Hz), 6.89-6.94(2H,m), 7.04(1H,dd,J=7.3 Hz and 7.4 Hz), 7.14(1H,s), 9.29(1H,br.s), 11.82(1H,br.s).

Example 33 Ethyl 4-(2-ethoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0492] The title compound was prepared from 2-ethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0493] MP: 203° C.

[0494] Anal. Calcd. for: C₂₀H₂₅N₃O₃:C,67.58;H,7.09;N,11.82.

[0495] Found: C,67.48;H,7.06;N,11.81.

[0496] MS(EI): 355(M⁺).

[0497]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.41(3H,t,J=7.3 Hz), 1.64-1.67(2H,m), 2.68-2.71(1H,m), 2.78-2.81(1H,m), 3.79(2H,q,J=7.3 Hz), 4.03-4.05(1H,m), 4.10-4.12(1H,m), 5.48(1H,s), 6.74(1H,dd,J=7.3 Hz and 7.4 Hz), 6.87(1H,d,J=7.3 Hz), 6.94(1H,d,J=7.3 Hz), 7.01(1H,dd,J=7.3 Hz and 7.4 Hz), 7.14(1H,s), 9.28(1H,br.s), 11.79(1H,br.s).

Example 34 Ethyl 4,7-dihydro-4-(2-propoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0498] The title compound was prepared from 2-propoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0499] MP: 205° C.

[0500] Anal. Calcd. for: C₂₁H₂₇N₃O₃:C,68.27;H,7.37;N,11.37.

[0501] Found: C,68.05;H,7.39;N,11.35.

[0502] MS(EI): 369(M⁺).

[0503]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.05(3H,t,J=7.3 Hz), 1.64-1.67(2H,m), 1.81-1.84(2H,m), 2.70-2.73(1H,m), 2.78-2.82(1H,m), 3.77(2H,q,J=7.3 Hz), 3.92(1H,q,J=7.3 Hz), 4.07(1H,q,J=7.3 Hz), 5.52(1H,s), 6.75(1H,dd,J=7.3 Hz and 7.4 Hz), 6.88(1H,d,J=7.3 Hz), 6.94(1H,d,J=7.3 Hz), 7.01(1H,dd,J=7.3 Hz and 7.4 Hz), 7.11(1H,s), 9.28(1H,br.s), 11.79(1H,br.s).

Example 35 Ethyl 4,7-dihydro-4-(2-isopropyloxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0504] The title compound was prepared from 2-isopropyloxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0505] MP: 210° C.

[0506] Anal. Calcd. for: C₂₁H₂₇N₃O₃:C,68.27;H,7.37;N,11.37.

[0507] Found: C,67.93;H,7.39;N,11.32.

[0508] MS(EI): 369(M⁺).

[0509]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.25(3H,d,J=6.8 Hz), 1.39(3H,d,J=6.8 Hz), 1.64-1.69(2H,m), 2.68-2.72(1H,m), 2.78-2.82(1H,m), 3.77(2H,q,J=7.3 Hz), 4.64-4.67(1H,m), 5.45(1H,s), 6.73(1H,dd,J=7.3 Hz and 7.4 Hz), 6.89-6.90(3H,m), 7.15(1H,s), 9.27(1H,br.s), 11.77(1H,br.s).

Example 36 Ethyl 4-(2-butoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0510] The title compound was prepared from 2-butoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0511] MP: 171° C.

[0512] Anal. Calcd. for: C₂₂H₂₉N₃O₃:C,68.90;H,7.62;N,10.96.

[0513] Found: C,68.66;H,7.63;N,10.89.

[0514] MS(EI): 383(M⁺).

[0515]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 0.95-0.99(6H,m), 1.52-1.80(6H,m), 2.69-2.71(1H,m), 1.76-1.80(1H,m), 3.77(2H,q,J=7.3 Hz), 3.95-3.98(1H,m), 4.07-4.10(1H,m), 5.51(1H,s), 6.74(1H,dd,J=7.3 Hz and 7.4 Hz), 6.88-6.94(2H,m), 7.01(1H,dd,J=7.3 Hz and 7.4 Hz), 7.10(1H,s), 9.28(1H,br.s), 11.79(1H,br.s).

Example 37 Ethyl 4-(2-cyclopentyloxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0516] The title compound was prepared from 2-cyclopentyloxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0517] MP: 195° C.

[0518] Anal. Calcd. for: C₂₃H₂₉N₃O₃:C,69.85;H,7.39;N,10.62.

[0519] Found: C,69.63;H,7.28;N,10.61.

[0520] MS(EI): 395(M⁺).

[0521]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.65-1.98(8H,m), 2.66-2.78(2H,m), 3.76(2H,q,J=7.3 Hz), 4.89-4.93(1H,m), 5.43(1H,s), 6.72(1H,dd,J=7.3 Hz and 7.4 Hz), 6.88-6.93(2H,m), 7.00(1H,dd,J=7.3 Hz and 7.4 Hz), 7.10(1H,s), 9.28(1H,br.s), 11.77(1H,br.s)

Example 38 Ethyl 4-(2-benzyloxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0522] The title compound was prepared from 2-benzyloxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0523] MP: 128° C.

[0524] Anal. Calcd. for: C₂₅H₂₇N₃O₃:C,71.92;H,6.52;N,10.06.

[0525] Found: C,71.66;H,6.73;N,9.85 .

[0526] MS(EI): 417(M⁺).

[0527]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.64-1.67(2H,m), 2.70-2.73(1H,m), 2.80-2.83(1H,m), 3.80(2H,q,J=7.3 Hz), 5.20(2H,d,J=30 Hz), 5.60(1H,s), 6.78(1H,dd,J=7.3 Hz and 7.4 Hz), 6.96-7.03(3H,m), 7.08(1H,s), 7.35(1H,dd,J=7.3 Hz and 7.4 Hz), 7.40-7.43(2H,m), 7.52-7.55(2H,m), 9.30(1H,br.s), 11.79(1H,br.s).

Example 39 Ethyl 4,7-dihydro-4-(2-methylthiophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0528] A solution of 2-methylthiobenzaldehyde (20 g), Meldrum's acid (19 g), ethyl 3-ketohexanoate (21 g) and ammonium acetate (11 g) in acetic acid (130 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (9.7 g). To a solution of dimethylformamide (1.3 g) in chloroform (5 mL) were added phosphorus oxychloride (1.7 mL) and a solution of the obtained colorless crystals (1.5 g) in chloroforom (10 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (18.5 g) solution was added and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals (0.9 g). To a solution of the obtained colorless crystals (0.9 g) in pyridine (10 mL) was added hydrazine (0.27 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (230 mg) as colorless crystals.

[0529] MP: 198° C.

[0530] Anal. Calcd. for: C₁₉H₂₃N₃O₂S: C,63.84;H,6.49;N,11.75.

[0531] Found: C,63.56;H,6.45;N,11.64.

[0532] MS(EI): 357(M⁺).

[0533]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.82(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.62-1.68(2H,m), 2.48(3H,s), 2.67-2.71(1H,m), 2.79-2.83(1H,m), 3.74(2H,q,J=7.3 Hz), 5.54(1H,s), 6.99-7.06(3H,m), 7.22-7.25(2H,m), 9.38(1H,br.s), 11.86(1H,br.s).

Example 40 Ethyl 4,7-dihydro-4-(2-methylsulfinylphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0534] To a solution of ethyl 4,7-dihydro-4-(2-methylthio)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (100 mg) in tetrahydrofuran (3.0 mL) was added metachloroperbenzoic acid (60 mg) and the mixture was stirred at −78° C. for 30 minutes. An aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give colorless crystals. By recrystallization from ethyl acetate, the title compound (50 mg) was obtained as colorless crystals.

[0535] MP: 216° C.

[0536] Anal. Calcd. for: C₁₉H₂₃N₃O₃S: C,61.10;H,6.21;N,11.25.

[0537] Found: C,61.32;H,6.18;N,10.99.

[0538] MS(EI): 373(M⁺).

[0539]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91 (3H,t,J=7.3 Hz),

[0540] 0.97(3H,t,J=7.3 Hz), 1.64-1.68(2H,m), 2.69-2.72(1H,m), 2.72(3H,s), 2.76-2.79(1H,m), 3.90(2H,q,J=7.3 Hz), 5.36(1H,s), 7.15(1H,dd,J=7.3 Hz and 7.4 Hz), 7.20(1H,s), 7.37-7.39(2H,m), 7.85(1H,dd,J=7.3 Hz and 7.4 Hz), 9.59(1H,br.s), 12.04(1H,br.s).

Example 41 Ethyl 4,7-dihydro-4-(2-nitrophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0541] The title compound was prepared from 2-nitrobenzaldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0542] MP: 218° C.

[0543] Anal. Calcd. for: C₁₈H₂₀N₄O₄:C,60.66;H,5.66;N,15.72.

[0544] Found: C,60.25;H,5.65;N,15.44.

[0545] MS(EI): 356(M⁺).

[0546]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.80(3H,t,J=7.3 Hz), 0.95(3H,t,J=7.3 Hz), 1.59-1.64(2H,m), 2.69-2.73(1H,m), 2.77-2.80(1H,m), 3.72(2H,q,J=7.3 Hz), 5.45(1H,s), 7.28-7.33(3H,m), 7.56(1H,dd,J=7.3 Hz and 7.4 Hz), 7.76(1H,d,J=7.3 Hz), 9.64(1H,br.s), 10.07(1H,br.s).

Example 42 Ethyl 4-(2-cyanophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0547] The title compound was prepared from 2-cyanobenzaldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0548] MP: 211° C.

[0549] Anal. Calcd. for: C₁₉H₂₀N₄O₂:C,67.84;H,5.99;N,16.66.

[0550] Found: C,67.49;H,6.14;N,16.23.

[0551] MS(EI): 336(M⁺).

[0552]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 0.94(3H,t,J=7.3 Hz), 1.61-1.67(2H,m), 2.71-2.73(1H,m), 2.79-2.82(1H,m), 3.80(2H,q,J=7.3 Hz), 5.48(1H,s), 7.21-7.29(2H,m), 7.28(1H,dd,J=7.3 Hz and 7.4 Hz), 7.55(1H,dd,J=7.3 Hz and 7.4 Hz), 7.70(1H,d,J=7.3 Hz), 9.63(1H,br.s), 12.07(1H,br.s).

Example 43 Ethyl 4-(2,3-difluorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0553] The title compound was prepared from 2,3-difluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0554] MP: 207° C.

[0555] Anal. Calcd. for: C₁₈H₁₉F₂N₃O₂ 1/5 H₂O:C,61.60;H,5.57;N,11.97.

[0556] Found: C,61.41;H,5.56;N,11.59.

[0557] MS(EI): 347(M⁺).

[0558]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-0.97(6H,m), 1.60-1.66(2H,m), 2.68-2.71(1H,m), 2.79-2.82(1H,m), 3.83(2H,q,J=7.3 Hz), 5.45(1H,s), 6.87(1H,dd,J=7.3 Hz and 7.4 Hz), 7.03-7.13(2H,m), 7.76(1H,s), 9.55(1H,br.s), 12.03(1H,br.s).

Example 44 Ethyl 4-(2,3-dichlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0559] The title compound was prepared from 2,3-dichlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0560] MP: 220° C.

[0561] Anal. Calcd. for: C₁₈H₁₉Cl₂N₃O₂:C,56.85;H,5.04;N,11.05.

[0562] Found: C,56.35;H,5.00;N,11.01.

[0563] MS(EI): 380(M⁺).

[0564]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 0.99(3H,t,J=7.3 Hz), 1.66-1.69(2H,m), 2.74-2.77(1H,m), 2.82-2.86(1H,m), 3.81(2H,q,J=7.3 Hz), 5.66(1H,s), 7.10(1H,d,J=7.3 Hz), 7.24(1H,dd,J=7.3 Hz and 7.4 Hz), 7.31(1H,s), 7.38(1H,d,J=7.3 Hz), 9.59(1H,br.s), 12.04(1H,br.s).

Example 45 Ethyl 4-(3-fluoro-2-methylphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0565] The title compound was prepared from 3-fluoro-2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0566] MP: 159-162° C.

[0567] Anal. Calcd. for: C₁₉H₂₂FN₃O₃ 3/10 H₂O:C,65.42;H,6.53;N,12.05.

[0568] Found: C,65.56;H,6.29;N,12.40.

[0569] MS(EI): 343(M⁺).

[0570]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89 (3H,t,J=7.3 Hz), 0.97 (3H,t,J=7.3 Hz), 1.64(2H,m), 2.36(3H,s), 2.67-2.84(2H,m), 3.80(2H,q,J=7.3 Hz), 5.35(1H,s), 6.86(2H,d,J=8.8 Hz), 7.07(1H,dd,J=7.3 Hz and 7.4 Hz), 7.23(1H,s), 9.42(1H,br.s), 11.94(1H,br.s).

[0571] IR(KBr): ν=3265,3193,2966,2934,1668,1591,1520,1466,1240 cm ⁻¹.

Example 46 Ethyl 4-(2,3-dimethoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0572] The title compound was prepared from 2,3-dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0573] MP: 205-206° C.

[0574] Anal. Calcd. for: C₂₀H₂₅N₃O₄:C,64.67;H,6.78;N,11.31.

[0575] Found: C,64.76;H,6.81;N,11.15.

[0576] MS(EI): 371(M⁺).

[0577]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90(3H,t,J=7.4 Hz), 0.98(3H,t,J=7.3 Hz), 1.66-1.68(2H,m), 2.68-2.70(1H,m), 2.80-2.83(1H,m), 3.77(3H,s), 3.80(3H,s), 3.80-3.85(2H,m), 5.44(1H,s), 6.58(1H,d,J=7.3 Hz), 6.76(1H,d,J=6.8 Hz), 6.88(1H,dd,J=7.3 Hz and 7.4 Hz), 7.11(1H,s), 9.32(1H,br.s), 11.83(1H,br.s).

Example 47 Ethyl 4-(2-chloro-3-trifluoromethylphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0578] The title compound was prepared from 2-chloro-3-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0579] MP: 236-238° C.

[0580] Anal. Calcd. for: C₁₉H₁₉ClF₃N₃O₂:C,55.15;H,4.63;N,10.15.

[0581] Found: C,55.07;H,4.55;N,10.13.

[0582] MS(EI): 413(M⁺).

[0583]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.82(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.65(2H,m), 2.70-2.90(2H,m), 3.65-3.85(2H,m), 5.72(1H,s), 7.29(1H,s), 7.41-7.42(2H,m), 7.59-7.61(1H,m), 9.62(1H,br.s), 12.05(1H,br.s).

Example 48 Ethyl 4-(2-chloro-4-fluorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0584] The title compound was prepared from 2-chloro-4-fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0585] MS(EI): 363(M⁺).

[0586]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.62-1.67(2H,m), 2.66-2.80(2H,m), 3.77(2H,q,J=7.3 Hz), 5.54(1H,s), 7.08-7.13(2H,m), 7.25(1H,s), 7.32(1H,dd,J=2.5 Hz and 8.8 Hz), 9.53(1H,br.s), 11.99(1H,br.s).

Example 49 Ethyl 4-(2,5-difluorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0587] The title compound was prepared from 2,5-difluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0588] MP: 168-169° C.

[0589] MS(EI): 347(M⁺).

[0590]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92-0.99(6H,m), 1.62-1.68(2H,m), 2.67-2.71(1H,m), 2.85-2.88(1H,m), 3.80-3.91(2H,m), 4.03(1H,q,J=6.8 Hz), 5.40(1H,s), 6.77-6.80(1H,m), 6.98-7.00(1H,m), 7.12-7.16(1H,m), 7.26(1H,s), 9.59(1H,br.s), 12.06(1H,br.s).

Example 50 Ethyl 4-(2,5-dichlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0591] The title compound was prepared from 2,5-dichlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0592] MP: 162° C.

[0593] Anal. Calcd. for: C₁₈H₁₉Cl₂N₃O₂ 1/2 H₂O:C,55.54;H,5.18;N,10.79.

[0594] Found: C,55.50;H,5.50;N,11.17.

[0595] MS(EI): 380(M⁺).

[0596]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 0.98(3H,t,J=7.3 Hz), 1.62-1.66(2H,m), 2.64-2.67(1H,m), 2.86-2.90(1H,m), 3.81(2H,q,J=7.3 Hz), 5.55(1H,s), 7.04(1H,s), 7.18(1H,d,J=7.3 Hz), 7.28(1H,s), 7.41(1H,d,J=7.3 Hz), 9.61(1H,br.s), 12.06(1H,br.s).

Example 51 Ethyl 4-(5-fluoro-2-methoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0597] The title compound was prepared from 5-fluoro-2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0598] MP: 164-167° C.

[0599] Anal. Calcd. for: C₁₉H₂₂FN₃O₃:C,63.50;H,6.17;N,11.69.

[0600] Found: C,63.24;H,6.09;N,11.70.

[0601] MS(EI): 359(M⁺).

[0602]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.3 Hz), 0.98(3H,t,J=7.3 Hz), 1.64-1.69(2H,m), 2.62-2.91(2H,m), 3.79(2H,q,J=7.3 Hz), 3.85(3H,s), 5.44(1H,s), 6.33(1H,dd,J=3.0 Hz and 7.8 Hz), 6.83-6.91(2H,m), 7.17(1H,s), 9.41(1H,br.s), 11.89(1H,br.s).

[0603] IR(KBr): ν=3252,2955,1657,1510,1232,1074 cm⁻¹.

Example 52 Ethyl 4-(2-chloro-5-methoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0604] The title compound was prepared from 2-chloro-5-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0605] MP: 182° C.

[0606] Anal. Calcd. for: C₁₉H₂₂ClN₃O₃:C,60.72;H,5.90;N,11.18.

[0607] Found: C,60.58;H,5.88;N,11.07.

[0608] MS(EI): 375(M⁺)

[0609]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 0.99(3H,t,J=7.3 Hz), 1.64-1.69(2H,m), 2.64-2.67(1H,m), 2.87-2.90(1H,m), 3.79(2H,q,J=7.3 Hz), 3.86(3H,s), 5.44(1H,s), 6.85(1H,d,J=7.3 Hz), 6.94(1H,d,J=7.3 Hz), 7.10(1H,dd,J=2.9 Hz and 7.3 Hz), 7.17(1H,s), 9.43(1H,br.s), 11.91(1H,br.s).

Example 53 Ethyl 4-(2,5-dimethoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0610] The title compound was prepared from 2,5-dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0611] MP: 169-170° C.

[0612] MS(EI): 371(M⁺).

[0613]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 0.98(3H,t,J=7.3 Hz), 1.68-1.70(2H,m), 2.49-2.54(1H,m), 2.94-2.97(1H,m), 3.57(3H,s), 3.79-3.83(2H,m), 3.80(3H,s), 4.02(1H,q,J=7.3 Hz), 5.43(1H,s), 6.49(1H,d,J=2.9 Hz), 6.59(1H,dd,J=2.9 Hz and 8.8 Hz), 6.82(1H,d,J=8.8 Hz), 7.14(1H,s), 9.32(1H,br.s), 11.83(1H,br.s).

Example 54 Ethyl 4-(2,6-difluorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0614] The title compound was prepared from 2,6-difluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0615] MP: 185° C.

[0616] Anal. Calcd. for: C₁₈H₁₉F₂N₃O₂ 1/2 H₂O:C,60.67;H,5.66;N,11.79.

[0617] Found: C,60.68;H,5.46;N,11.61.

[0618] MS(EI): 347(M⁺).

[0619]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-0.97(6H,m), 1.54-1.58(2H,m), 2.51-2.54(1H,m), 2.76-2.81(1H,m), 3.82(2H,q,J=7.3 Hz), 5.53(1H,s), 6.90(2H,dd,J=7.3 Hz and 7.3 Hz), 7.16(1H,d,J=7.3 Hz), 7.20(1H,s), 9.50(1H,br.s), 11.96(1H,br.s).

Example 55 Ethyl 4-(2,6-dichlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0620] The title compound was prepared from 2,6-dichlorobenzaldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0621] MP: 202° C.

[0622] Anal. Calcd. for: C₁₈H₁₉Cl₂N₃O₂ 3/10 H₂O:C,56.06;H,5.12;N,10.90.

[0623] Found: C,56.28;H,5.46;N,10.78.

[0624] MS(EI): 380(M⁺).

[0625]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83(3H,t,J=7.3 Hz), 0.92(3H,t,J=7.3 Hz), 1.57-1.62(2H,m), 2.47-2.51(1H,m), 2.77-2.80(1H,m), 3.74(2H,q,J=7.3 Hz), 6.03(1H,s), 7.05(1H,s), 7.13(1H,dd,J=7.3 Hz and 7.4 Hz), 7.22(1H,d,J=7.3 Hz), 7.39(1H,d,J=7.3 Hz), 9.53(1H,br.s), 11.93(1H,br.s).

Example 56 Ethyl 4-(2-chloro-6-fluorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0626] The title compound was prepared from 2-chloro-6-fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0627] MP: 180-183° C.

[0628] MS(EI): 363(M⁺).

[0629]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=6.9 Hz), 0.94(3H,t,J=7.3 Hz), 1.56-1.61(2H,m), 2.50-2.85(2H,m), 3.80(2H,q,J=7.3 Hz), 5.75(1H,s), 7.01-7.17(4H,m), 9.52(1H,br.s), 11.97(1H,br.s).

[0630] IR(KBr): ν=3265,1591,1518,1456,1228,1097 cm³¹ .

Example 57 Ethyl 4,7-dihydro-6-propyl-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Dihydrocloride

[0631] The title compound was prepared from pyridine-3-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0632] MP: 251° C.

[0633] Anal. Calcd. for: C₁₇H₂₀N₄O₂.2HCl: C,52.99;H,5.76;N,14.54.

[0634] Found: C,52.99;H,5.67;N,14.44.

[0635] MS(EI): 312(M⁺).

[0636]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.09(3H,t,J=7.3 Hz), 1.52-1.61(2H,m), 2.66-2.71(2H,m), 3.93-4.00(2H,m), 5.24(1H,s), 7.90(1H,dd,J=7.3 Hz and 7.4 Hz), 8.31-8.35(2H,m), 8.66-8.69(2H,m), 10.35(1H,br.s).

Example 58 Ethyl 4,7-dihydro-6-propyl-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate dihydrocloride

[0637] The title compound was prepared from pyridine-4-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0638] MP: 266° C.

[0639] Anal. Calcd. for: C₁₇H₂₀N₄O₂2HCl: C,52.99;H,5.76;N,14.54.

[0640] Found: C,52.63;H,5.65;N,14.69.

[0641] MS(EI): 312(M⁺).

[0642]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.12(3H,t,J=7.3 Hz), 1.52-1.59(2H,m), 2.64-2.72(2H,m), 4.01(2H,q,J=7.3 Hz), 5.30(1H,s), 7.76(2H,d,J=6.4 Hz), 8.66(1H,s), 8.72(2H,d,J=6.4 Hz), 10.39(1H,br.s).

Example 59 Ethyl 4-(furan-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0643] The title compound was prepared from furan-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0644] MP: 108-111° C.

[0645] MS(EI): 301(M⁺).

[0646]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.05(3H,t,J=6.8 Hz), 1.58(2H,q,J=7.3 Hz), 2.66-2.72(2H,m), 3.50(3H,br.s), 3.94(2H,q,J=6.8 Hz), 5.21(1H,s), 5.78(1H,d, J=2.9 Hz), 6.23(1H,s), 6.24(2H,s), 7.75(1H,s), 7.38(1H,s), 9.42 (1H,br.s).

[0647] IR(KBr): ν=3207,2962,1703,1479,1348,1205,1076,866 cm⁻¹.

Example 60 Ethyl 4-(furan-3-yl)-4,7-dihydro-4-(furan-3-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0648] The title compound was prepared from furan-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0649] MP: 121-123° C.

[0650] Anal. Calcd. for: C₁₆H₁₉N₃O₃C₄H₄O₄:C,57.54;H,5.55;N,10.07.

[0651] Found: C,57.14;H,5.55;N,10.37.

[0652] MS(EI): 301(M⁺).

[0653]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90(3H,t,J=7.3 Hz), 1.08(3H,t,J=7.4 Hz), 1.55-1.57(2H,m), 2.62-2.70(2H,m), 3.36(1H,br.s), 3.50(2H,br.s), 3.97(2H,q,J=7.3 Hz), 5.06(1H,s), 6.16(1H,s), 6.24(2H,s), 7.13(1H,s), 7.35(1H,s), 7.40(1H,s), 9.31(1H,br.s).

[0654] IR(KBr): ν=3350,2972,1591,1467,1361,1203,1089 cm⁻¹.

Example 61 Ethyl 4,7-dihydro-4-(2-methylfuran-3-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0655] The title compound was prepared from 2-methylfuran-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0656] MP: 123-125° C.

[0657] Anal. Calcd. for: C₁₇H₂₁N₃O₃ 2/5 H₂O:C,63.30;H,6.81;N,13.03.

[0658] Found: C,63.51;H,6.64;N,12.96.

[0659] MS(EI): 315(M⁺).

[0660]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.3 Hz), 1.08(3H,t,J=7.3 Hz), 1.58-1.60(2H,m), 2.20(3H,s), 2.55-2.75(2H,m), 3.92(2H,q,J=7.3 Hz), 4.99(1H,s), 5.96(1H,s), 7.21(2H,s), 9.26(1H,br.s), 11.91(1H,br.s).

[0661] IR(KBr): ν=3265,3198,2964,1591,1514,1224,1209,1093 cm⁻¹.

Example 62 Ethyl 4,7-dihydro-6-propyl-4-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0662] The title compound was prepared from thiophene-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0663] MP: 129-131° C.

[0664] Anal. Calcd. for: C₁₆H₁₉N₃O₂SC₄H₄O₄ 1/4 H₂O:C,54.85;H,5.41;N,9.59.

[0665] Found: C,54.59;H,5.22;N,9.97.

[0666] MS(EI): 317(M⁺).

[0667]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.4 Hz), 1.06(3H,t,J=7.3 Hz), 1.58-1.60(2H,m), 2.72-2.74(2H,m), 3.50(3H,br.s), 3.94(2H,q,J=7.4 Hz), 5.44(1H,s), 6.25(2H,s), 6.69(1H,s), 6.81(1H,d), 7.15(1H,d), 7.37(1H,s), 9.50(1H,br.s).

Example 63 Ethyl 4,7-dihydro-4-(3-methylthiophen-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0668] The title compound was prepared from 3-methylthiophene-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0669] MP: 125° C.

[0670] Anal. Calcd. for: C₁₇H₂₁N₃O₂S H₂O:C,58.43;H,6.63;N,12.02.

[0671] Found: C,58.59;H,6.33;N,12.12.

[0672] MS(EI): 331(M⁺).

[0673]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.9 6(3H,t,J=7.4 Hz), 0.98(3H,t,J=7.3 Hz), 1.60-1.63(2H,m), 2.22(3H,s), 2.83-2.90(2H,m), 3.88(2H,q,J=7.3 Hz), 5.42(1H,s), 6.68(1H,d,J=4.9 Hz), 7.02(1H,d,J=5.4 Hz), 7.29(1H,s), 9.45(1H,br.s), 11.98(1H,br.s).

[0674] IR(KBr): ν=3267,3196,2968,1664,1510, 1267,1201,1091 cm⁻¹.

Example 64 Ethyl 4-(5-chlorothiophen-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0675] The title compound was prepared from 5-chlorothiophene-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0676] MP: 129-131° C.

[0677] Anal. Calcd. for: C₁₆H₁₈N₃O₂SC₄H₄O₄:C,51.33;H,4.74;N,8.98.

[0678] Found: C,51.34;H,4.54;N,9.03.

[0679] MS(EI): 351(M⁺).

[0680]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.92 (3H,t,J=7.3 Hz), 1.10(3H,t,J=6.9 Hz), 1.59-1.61(2H,m), 2.57-2.82(2H,m), 3.50(2H,br.s), 3.38(1H,s), 3.98(2H,q,J=6.9 Hz), 5.36(1H,s), 6.25(2H,s), 6.53(1H,d,J=3.9 Hz), 6.80(1H,d,J=3.4 Hz), 7.42(1H,s), 9.60 (1H,br.s).

[0681] IR(KBr): ν323205,2964,2629,1618,1471,1363,1205,1080,889,652 cm⁻¹.

Example 65 Ethyl 4,7-dihydro-6-propyl-4-(thiophen-3-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0682] The title compound was prepared from thiophene-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0683] MP: 141-143° C.

[0684] Anal. Calcd. for: C₁₆H₁₉N₃O₂SC₄H₄O₄:C,54.42;H,5.35;N,9.69.

[0685] Found: C,54.17;H,5.23;N,9.66.

[0686] MS(EI): 317(M⁺).

[0687]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.03(3H,t,J=6.8 Hz), 1.59-1.61(2H,m), 2.60-2.78(2H,m), 3.50(2H,br.s), 3.91(2H,q,J=6.8 Hz), 5.22(2H,s), 6.26(2H,s), 6.84-6.88(2H,m), 7.29(1H,dd,J=3.0 Hz and 4.9 Hz), 7.33(1H,s), 12.0(1H,br.s).

[0688] IR(KBr): ν=3346,2980,2611,1697,1467,1361,1205,1087 cm⁻¹.

Example 66 Ethyl 4,7-dihydro-4-(naphthalen-1-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0689] The title compound was prepared from naphthalene-1-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0690] MP: 182° C.

[0691] Anal. Calcd. for: C₂₂H₂₃N₃O₂:C,73.11;H,6.41;N,11.63.

[0692] Found: C,72.95;H,6.47;N,11.40.

[0693] MS(EI): 361(M⁺).

[0694]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.62(3H,t,J=7.3 Hz), 1.00(3H,t,J=7.3 Hz), 1.69-1.73(2H,m), 2.73-2.76(1H,m), 2.84-2.87(1H,m), 3.67(2H,q,J=7.3 Hz), 5.95(1H,s), 7.03(1H,s), 7.23(1H,d,J=7.3 Hz), 7.36(1H,dd,J=7.3 Hz and 7.4 Hz), 7.49(1H,dd,J=7.3 Hz and 7.4 Hz), 7.57(1H,dd,J=7.3 Hz and 7.4 Hz), 7.65(1H,d,J=7.3 Hz), 7.88(1H,d,J=7.3 Hz), 8.40(1H,d,J=7.3 Hz), 9.45(1H,br.s), 11.82(1H,br.s).

Example 67 Ethyl 4,7-dihydro-4-(naphthalen-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0695] The title compound was prepared from naphthalene-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0696] MP: 136-138° C.

[0697] Anal. Calcd. for: C₂₂H₂₃N₃O₂C₄H₄O₄ 1/4 H₂O:C,64.79;H,5.75;N,8.72.

[0698] Found: C,64.86;H,5.57;N,8.99.

[0699] MS(EI): 361(M⁺).

[0700]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92-0.98(6H,m), 1.64-1.68(2H,m), 2.72-2.80(2H,m), 3.50(2H,br.s), 3.80(2H,q,J=7.3 Hz), 5.27(1H,s), 6.25(2H,s), 7.23(1H,s), 7.31(1H,d,J=8.3 Hz), 7.41-7.43(2H,m), 7.57(1H,s), 7.73-7.77(2H,m), 9.47(1H,br.s).

[0701] IR(KBr): ν=3202,2962,1701,1464,1359,1222 cm⁻¹.

Example 68 Ethyl 4,7-dihydro-4-(2-methoxynaphthalen-1-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0702] The title compound was prepared from 2-methoxynaphthalene-1-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0703] MP: 188-191° C.

[0704] Anal. Calcd. for: C₂₃H₂₅N₃O₃ 2/5 H₂O:C,69.29;H,6.52;N,10.54.

[0705] Found: C,69.35;H,6.62;N,10.21.

[0706] MS(EI): 391(M⁺).

[0707]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.71(3H,t,J=7.3 Hz), 0.95(3H,t,J=7.3 Hz), 1.62-1.63(2H,m), 2.49-2.86(2H,m), 3.61(2H,q,J=7.3 Hz), 3.97(3H,s), 6.27(1H,s), 6.89(1H,s), 7.16-7.51(3H,m), 7.71-7.77(2H,m), 7.98(1H,s), 9.43(1H,br.s), 11.77(1H,br.s).

[0708] IR(KBr): ν=3258, 1655,1593, 1082 cm⁻¹.

Example 69 Ethyl 4-(2,3-dihydobenzo[b]furan-7-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0709] The title compound was prepared from 2,3-dihydobenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0710] MP: 194-196° C.

[0711] Anal. Calcd. for: C₂₀H₂₃N₃O₃:C,67.97;H,6.56;N,11.89.

[0712] Found: C,67.97;H,6.68;N,11.77.

[0713] MS(EI): 353(M⁺).

[0714]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.4 Hz), 0.97(3H,t,J=7.3 Hz), 1.66(2H,m), 2.67-2.70(1H,m), 2.82-2.84(1H,m), 3.15(2H,t,J=8.8 Hz), 3.83-3.86(2H,m), 4.55-4.58(2H,m), 5.29(1H,s), 6.64(1H,dd,J=7.3 Hz and 7.4 Hz), 6.72(1H,d,J=6.9 Hz), 6.93(1H,dd,J=7.3 Hz and 7.4 Hz), 7.20(1H,s), 9.32(1H,br.s), 11.86(1H,br.s).

Example 70 Ethyl 4-(5-bromo-2,3-dihydobenzo[b]furan-7-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0715] The title compound was prepared from 5-bromo-2,3-dihydobenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0716] MP: 200-210° C.

[0717] Anal. Calcd. for: C₂₀H₂₂BrN₃O₃:C,55.57;H,5.13;N,9.72.

[0718] Found: C,55.23;H,5.09;N,9.89.

[0719] MS(EI): 432(M⁺).

[0720]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93-0.98(6H,m), 1.64(2H,q,J=7.3 Hz), 2.63(1H,m), 2.88-2.90(1H,m), 3.16(2H,t,J=8.3 Hz), 3.85-3.87(2H,m), 4.57-4.60(2H,m), 5.23(1H,s), 6.78(1H,s), 7.11(1H,s), 7.22(1H,s), 9.44(1H,br.s), 11.94(1H,br.s)

Example 71 Ethyl 4-(5-chloro-2,3-dihydo-2-methylbenzo[b]furan-7-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0721] The title compound was prepared from 5-chloro-2,3-dihydo-2-methylbenzo[b] furan-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0722] MP: 155-158° C.

[0723] Anal. Calcd. for: C₂₁H₂₄N₃O₃C₄H₄O₄:C,57.95;H,5.45;N,8.11.

[0724] Found: C,57.57;H,5.28;N,8.47.

[0725] MS(EI): 401(M⁺).

[0726]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(6H,t,J=6.8 Hz), 1.03(3H,d,J=6.3 Hz), 1.65(2H,m), 2.40-2.73(2H,m), 2.87(1H,m), 3.29(1H,m), 3.50(3H,br.s), 3.84(2H,q,J=6.8 Hz), 5.05(1H,m), 5.23(1H,s), 6.25(2H,s), 6.64(1H,s), 6.95(1H,s), 7.20(1H,d,J=4.4 Hz), 9.43(1H,br.s).

[0727] IR(KBr): ν=3207,2976,1589,1462,1201,1082 cm⁻¹.

Example 72 Ethyl 4-(2H-1-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0728] The title compound was prepared from 2H-1-benzopyran-8-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0729] MP: 194° C.

[0730] Anal. Calcd. for: C₂₁H₂₃N₃O₃:C,69.02;H,6.34;N,11.50.

[0731] Found: C,68.60;H,6.43;N,11.25.

[0732] MS(EI): 194(M⁺).

[0733]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.64-1.68(2H,m), 2.62-2.66(1H,m), 2.80-2.84(1H,m), 3.81(2H,q,J=7.3 Hz), 4.85(2H,dd,J=2.0 Hz and 9.8 Hz), 5.39(1H,s), 5.89(1H,d,J=9.8 Hz), 6.46(1H,d,J=9.8 Hz), 6.67-6.80(3H,m), 7.18(1H,s), 9.31(1H,br.s), 11.86(1H,br.s).

Example 73 Ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0734] The title compound was prepared from 3,4-dihydro-2H-benzopyran-8-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0735] MP: 208° C.

[0736] Anal. Calcd. for: C₂₁H₂₅N₃O₃ 1/2 H₂O:C,67.01;H,6.96;N,11.16.

[0737] Found: C,67.41;H,6.84;N,10.93.

[0738] MS(EI): 367(M⁺).

[0739]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 1.92-1.96(2H,m), 2.67-2.82(4H,m), 3.80(2H,q,J=7.3 Hz), 4.22-4.26(2H,m), 5.41(1H,s), 6.61(1H,dd,J=7.3 Hz and 7.4 Hz), 6.71-6.75(2H,m), 7.17(1H,s), 9.25(1H,br.s), 11.80(1H,br.s).

Example 74 Ethyl 4,7-dihydro-6-propyl-4-(quinolin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0740] The title compound was prepared from quinoline-4-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0741] MP: 198° C.

[0742] Anal. Calcd. for: C₂₁H₂₂N₄O₂ 2/5 H₂O:C,68.24;H,6.22;N,15.16.

[0743] Found: C,68.39;H,6.04;N,14.83.

[0744] MS(EI): 362(M⁺).

[0745]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.61(3H,t,J=7.3 Hz), 1.02(3H,t,J=7.3 Hz), 1.68-1.72(2H,m), 2.76-2.78(1H,m), 2.86-2.89(1H,m), 3.66-3.68(2H,m), 5.97(1H,s), 7.07(1H,s), 7.17(1H,d,J=4.4 Hz), 7.65(1H,dd,J=7.3 Hz and 7.4 Hz), 7.74(1H,dd,J=7.3 Hz and 7.4 Hz), 7.99(1H,d,J=7.3 Hz), 8.48(1H,d,J=7.8 Hz), 8.73(1H,d,J=4.4 Hz), 9.61(1H,br.s), 11.94(1H,br.s)

Example 75 Ethyl 4-(benzo[b]thiophen-3-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0746] The title compound was prepared from benzo[b]thiophene-3-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0747] MP: 222° C.

[0748] Anal. Calcd. for: C₂₀H₂₁N₃O₂S: C,65.37;H,5.76;N,11.44.

[0749] Found: C,65.11;H,5.31;N,11.83.

[0750] MS(EI): 238(M⁺).

[0751]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.64(3H,t,J=7.3 Hz), 1.20(3H,t,J=7.3 Hz), 1.56-1.58(2H,m), 2.66-2.78(2H,m), 4.11(2H,q,J=7.3 Hz), 4.89(1H,s), 7.42-7.50(2H,m), 7.55(1H,s), 7.61(1H,s), 7.96-8.01(2H,m), 10.32(1H,br.s), 12.13(1H,br.s).

Example 76 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0752] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 39.

[0753] MP: 207° C.

[0754] Anal. Calcd. for: C₁₈H₁₉N₅O₃:C,61.18;H,5.42;N,19.82.

[0755] Found: C,61.06;H,5.50;N,19.66.

[0756] MS(EI): 353(M⁺).

[0757]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.77(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 2.72-2.77(1H,m), 2.82-2.86(1H,m), 3.79(2H,q,J=7.3 Hz), 5.68(1H,s), 7.11(1H,d,J=7.3 Hz), 7.22(1H,s), 7.51(1H,dd,J=7.3 Hz and 7.4 Hz), 7.78(1H,d,J=7.3 Hz), 9.66(1H,br.s), 12.01(1H,br.s).

Example 77 Ethyl 4-(1,3-benzdioxazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0758] The title compound was prepared from 1,3-benzdioxazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0759] MP: 203-207° C.

[0760] Anal. Calcd. for: C₁₉H₂₁N₃O₄ 1/10 H₂O:C,63.89;H,5.98;N,11.76.

[0761] Found: C,63.72;H,5.86;N,12.01.

[0762] MS(EI): 355(M⁺).

[0763]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.4 Hz), 1.61-1.67(2H,m), 2.64-2.82(2H,m), 3.80-3.88(2H,m), 5.28(1H,s), 5.99(1H,s), 6.00(1H,d,J=9.7 Hz), 6.50(1H,d,J=5.9 Hz), 6.65(1H,s), 6.65-6.69(1H,m), 7.25(1H,s), 9.40(1H,br.s), 11.94(1H,br.s).

[0764] IR(KBr): ν=3265,3188,2962,1662,1587,1514,1462,1253,1215,1066 cm⁻¹.

Example 78 Ethyl 4-(6-chloro-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0765] The title compound was prepared from 6-chloro-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-8-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0766] MS(EI): 430(M⁺).

[0767]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.4 Hz), 0.96(3H,t,J=7.3 Hz), 1.18(3H,s), 1.32(3H,s), 1.62-1.64(2H,m), 2.66-2.82(2H,m), 2.99(2H,s), 3.80(2H,t,J=7.3 Hz), 5.32(1H,s), 6.01(2H,s), 6.14(1H,s), 6.32(1H,s), 7.14(1H,s), 9.31(1H,br.s), 11.82(1H,br.s).

[0768] IR(KBr): ν=3281,2974,1672,1599,1520,1207,1155,1091 cm⁻¹.

Example 79 Ethyl 4-(6-chloro-3,4-dihydro-2,2,4-trimethyl-1,4-benzoxazin-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0769] The title compound was prepared from 6-chloro-3,4-dihydro-2,2,4-trimethyl-2H-1,4-benzoxazine-8-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0770] MS(EI): 444(M⁺).

[0771]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.20(6H,s), 1.35(3H,s), 1.63-1.65(2H,m), 2.83(2H,s), 3.00(2H,q,J=7.3 Hz), 5.34(1H,s), 6.26(2H,s), 6.43(1H,d,J=2.5 Hz), 7.13(1H,s), 9.33(1H,s), 11.82(1H,br.s).

[0772] IR(KBr): ν=3273,2974,1666,1597,1518,1458,1259,1211 cm⁻¹.

Example 80 Ethyl 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0773] The title compound was prepared from 2,3-dihydro-1,4-benzodioxin-6-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0774] MP: 147-149° C.

[0775] Anal. Calcd. for: C₂₀H₂₃N₃O₄C₄H₄O₄:C,59.37;H,5.60;N,8.66.

[0776] Found: C,59.12;H,5.63;N,8.57.

[0777] MS(EI): 369(M⁺).

[0778]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.3 Hz), 1.02(3H,t,J=6.8 Hz), 1.60(2H,q,J=7.3 Hz), 2.64-2.68(2H,m), 3.50(2H,br.s), 3.86(2H,q,J=7.3 Hz), 4.14(4H,s), 4.99(1H,s), 6.26(2H,s), 6.54(1H,s), 6.57(1H,d,J=7.8 Hz), 6.65(1H,d,J=7.8 Hz), 7.21(1H,s), 11.97(1H,br.s).

[0779] IR(KBr): ν=3211,2694,2878,2658,1697,1506,1466,1363,1302,1082cm⁻¹.

Example 81 Ethyl 4-(benzo[b]furan-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Maleate

[0780] The title compound was prepared from benzo[b]furan-2-aldehyde,

[0781] 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0782] MP: 123-125° C.

[0783] Anal. Calcd. for: C₂₀H₂₁N₃O₃C₄H₄O₄ 1/2 H₂O:C,61.19;H,5.43;N,8.92.

[0784] Found: C,61.02;H,5.41;N,9.27.

[0785] MS(EI): 351(M⁺).

[0786]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.96(3H,t,J=7.3 Hz), 1.02(3H,t,J=6.8 Hz), 1.63(2H,q,J=7.3 Hz), 2.73-2.76(2H,m), 3.50(3H,br.s), 3.93(2H,q,J=7.3 Hz), 5.36(1H,s), 6.24(2H,s), 6.43(1H,s), 7.10-7.21(2H,m), 7.41-7.48(3H,m), 9.51(1H,br.s).

[0787] IR(KBr): ν=3190,3080,2962,1705,1581,1454,1359,1195,883cm ⁻¹.

Example 82 Ethyl 4-(2-chlorophenyl)-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0788] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.

[0789] MP: 213° C.

[0790] Anal. Calcd. for: C₁₇H₁₈ClN₃O₂:C,61.54;H,5.47;N,12.66.

[0791] Found: C,61.54;H,5.46;N,12.68.

[0792] MS(EI): 331(M⁺).

[0793]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 1.21(3H,t,J=7.3 Hz), 2.78-2.84(2H,m), 3.78(2H,q,J=7.3 Hz), 5.58(1H,s), 7.07-7.12(2H,m), 7.18(1H,dd,J=7.3 Hz and 7.4 Hz), 7.25(1H,s), 7.34(1H,d,J=7.3 Hz), 9.52(1H,br.s), 11.97(1H,br.s)

Example 83 Ethyl 6-butyl-4-(2-chlorophenyl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0794] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.

[0795] MP: 209° C.

[0796] Anal. Calcd. for: C₁₉H₂₂ClN₃O₂ 1/5 H₂O:C,62.79;H,6.21;N,11.56.

[0797] Found: C,62.78;H,6.11;N,11.45.

[0798] MS(EI): 359(M⁺).

[0799]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 0.92(3H,t,J=7.3 Hz), 1.36-1.42(2H,m), 1.60-1.64(2H,m), 2.72-2.76(1H,m), 2.83-2.86(1H,m), 3.78(2H,q,J=7.3 Hz), 5.58(1H,s), 7.07-7.11(2H,m), 7.18(1H,dd,J=7.3 Hz and 7.4 Hz), 7.24(1H,s), 7.34(1H,d,J=7.3 Hz), 9.49(1H,br.s), 11.96(1H,br.s).

Example 84 Methyl 4-(2-chlorophenyl)-4,7-dihydro-6-methoxymethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0800] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl 4-methoxyacetoacetate in the same manner as in Example 1.

[0801] MP: 160° C.

[0802] Anal. Calcd. for: C₁₆H₁₆ClN₃O₃:C,57.33;H,4.83;N,12.59.

[0803] Found: C,57.53;H,4.86;N,12.58.

[0804] MS(EI): 333(M⁺).

[0805]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.36(3H,s), 3.38(3H,s), 4.67(2H,s), 5.58(1H,s), 7.08-7.13(2H,m), 7.19(1H,dd,J=7.3 Hz and 7.4 Hz), 7.32-7.36(2H,m), 9.14(1H,br.s), 12.08(1H,br.s).

Example 85 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0806] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl benzoylacetoacetate in the same manner as in Example 1.

[0807] MP: 214° C.

[0808] Anal. Calcd. for: C₂₁H₁₈ClN₃O₂ 3/10 H₂O:C,65.47;H,4.87;N,10.91.

[0809] Found: C,65.29;H,4.73;N,10.93.

[0810] MS(EI): 379(M⁺).

[0811]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.57(3H,t,J=7.3 Hz), 3.52(2H,q,J=7.3 Hz), 5.65(1H,s), 7.14(1H,dd,J=7.3 Hz and 7.4 Hz), 7.27(1H,dd,J=7.3 Hz and 7.4 Hz), 7.37-7.40(8H,m), 9.53(1H,br.s), 12.04(1H,br.s).

Example 86 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-(4-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0812] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl (4-methoxybenzoyl)acetate in the same manner as in Example 1.

[0813] MP: 211° C.

[0814] Anal. Calcd. for: C₂₂H₂₀ClN₃O₃:C,64.47;H,4.92;N,10.25.

[0815] Found: C,64.30;H,5.00;N,10.24.

[0816] MS(EI): 409(M⁺).

[0817]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.64(3H,t,J=7.3 Hz), 3.56(2H,q,J=7.3 Hz), 3.79(3H,s), 5.63(1H,s), 6.95(2H,d,J=7.3 Hz), 7.13(1H,dd,J=7.3 Hz and 7.4 Hz), 7.24-7.38(6H,m), 9.45(1H,br.s), 12.03(1H,br.s).

Example 87 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0818] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl (thiophen-2-carbonyl) acetate in the same manner as in Example 1.

[0819] MP: 200° C.

[0820] Anal. Calcd. for: C₁₉H₁₆ClN₃O₂S: C,59.14;H,4.18;N,10.89.

[0821] Found: C,59.04;H,4.31;N,11.14.

[0822] MS(EI): 385(M⁺).

[0823]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.02(3H,t,J=7.3 Hz), 4.04(2H,q,J=7.3 Hz), 5.16(1H,s), 6.58(1H,d,J=7.3 Hz), 7.18-7.70(7H,m), 9.60(1H,br.s), 12.74(1H,br.s).

Example 88 Ethyl 6-benzyl-4-(2-chlorophenyl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0824] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4-phenylacetoacetate in the same manner as in Example 1.

[0825] MP: 247° C.

[0826] Anal. Calcd. for: C₂₂H₂₀ClN₃O₂0 1/5 H₂O:C,66.48;H,5.17;N,10.57.

[0827] Found: C,66.30;H,5.17;N,10.37.

[0828] MS(EI): 393(M⁺).

[0829]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.81(3H,t,J=7.3 Hz), 3.76(2H,q,J=7.3 Hz), 4.25(2H,s), 5.65(1H,s), 7.06-7.41(10H,m), 9.68(1H,br.s), 12.01(1H,br.s).

Example 89 Ethyl 6-ethyl-4,7-dihydro-4-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0830] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.

[0831] MP: 169° C.

[0832] Anal. Calcd. for: C₁₈H₂₁N₃O₃ 3/10 H₂O:C,64.97;H,6.54;N,12.63.

[0833] Found: C,64.86;H,6.84;N,12.33.

[0834] MS(EI): 327(M⁺).

[0835]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 1.18(3H,t,J=7.3 Hz), 2.73-2.76(1H,m), 2.81-2.85(1H,m), 3.74(2H,q,J=7.3 Hz), 3.85(3H,s), 5.46(1H,s), 6.76(1H,dd,J=7.3 Hz and 7.4 Hz), 6.89-6.94(2H,m), 7.04(1H,dd,J=7.3 Hz and 7.4 Hz), 7.14(1H,s), 9.32(1H,br.s), 11.82(1H,br.s).

Example 90 Ethyl 6-butyl-4,7-dihydro-4-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0836] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.

[0837] MP: 190° C.

[0838] Anal. Calcd. for: C₂₀H₂₅N₃O₃ 1/2 H₂O:C,65.91;H,7.19;N,11.53.

[0839] Found: C,65.92;H,7.07;N,11.88.

[0840] MS(EI): 355(M⁺).

[0841]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 0.93(3H,t,J=7.3 Hz), 1.38-1.44(2H,m), 1.59-1.64(2H,m), 2.64-2.68(1H,m), 2.85-2.90(1H,m), 3.81(2H,q,J=7.3 Hz), 3.85(3H,s), 5.47(1H,s), 6.76(1H,dd,J=7.3 Hz and 7.4 Hz), 6.89-6.94(2H,m), 7.04(1H,dd,J=7.3 Hz and 7.4 Hz), 7.14(1H,s), 9.29(1H,br.s), 11.82(1H,br.s).

Example 91 Methyl 4,7-dihydro-6-methoxymethyl-4-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0842] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and methyl 4-methoxyacetoacetate in the same manner as in Example 1.

[0843] MP: 186° C.

[0844] Anal. Calcd. for: C₁₇H₁₉N₃O₄ 1/5 H₂O:C,61.32;H,5.87;N,12.62.

[0845] Found: C,61.34;H,5.84;N,12.52.

[0846] MS(EI): 329(M⁺).

[0847]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.36(3H,s), 3.38(3H,s), 3.86(3H,s), 4.68(2H,s), 5.46(1H,s), 6.77(1H,dd,J=7.3 Hz and 7.4 Hz), 6.90-6.94(2H,m), 7.06(1H,dd,J=7.3 Hz and 7.4 Hz), 7.22(1H,s), 8.94(1H,br.s), 11.94(1H,br.s).

Example 92 Ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-phenyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0848] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.

[0849] MP: 195° C.

[0850] Anal. Calcd. for: C₂₂H₂₁N₃O₃:C,70.38;H,5.64;N,11.19.

[0851] Found: C,70.41;H,5.71;N,11.27.

[0852] MS(EI): 375(M⁺).

[0853]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.55(3H,t,J=7.3 Hz), 3.53(2H,q,J=7.3 Hz), 3.88(3H,s), 5.52(1H,s), 6.84(1H,dd,J=7.3 Hz and 7.4 Hz), 6.94(1H,d,J=7.3 Hz), 7.09(1H,dd,J=7.3 Hz and 7.4 Hz), 7.18(1H,d,J=7.3 Hz), 7.23(1H,s), 7.37-7.40(5H,m), 9.33(1H,br.s), 1.90(1H,br.s).

Example 93 4-(2-Chlorophenyl)-4,7-dihydro-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[0854] To an aqueous solution (50 mL) of nitromethane (50 g) was added an aqueous solution (50 mL) of n-butylaldehyde (59 g), and the mixture was stirred with heating at 60° C. for 6 hours. The reaction mixture was allowed to cool to ambient temperature, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give a brown oil (58 g). To a mixed solution of the obtained oil (50 g) in water (50 mL) and acetone (50 mL) was added sodium chromate (70 g). Under ice-cooling, concentrated sulfuric acid (46 mL) was added dropwise and the mixture was stirred for 5 hours. Ice-water (200 mL) was added and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-nitropentan-2-one (40 g) as a brown oil. A solution of 2-chlorobenzaldehyde (1.8 g), 3-aminopyrazole (1.0 g) and 1-nitropentan-2-one (1.4 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give the title compound (680 mg) as yellow crystals.

[0855] MP: 228° C.

[0856] Anal. Calcd. for: C₁₅H₁₅ClN₄O₂:C,56.52;H,4.74;N,17.58.

[0857] Found: C,56.26;H,4.91;N,17.64.

[0858] MS(EI): 318(M⁺).

[0859]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.02(3H,t,J=7.3 Hz), 1.70-1.73(2H,m), 2.89-2.91(1H,m), 2.99-3.02(1H,m), 5.90(1H,s), 7.09-7.21(3H,m), 7.39(1H,d,J=7.3 Hz), 7.44(1H,s), 10.84(1H,br.s), 12.43(1H,br.s).

Example 94 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[0860] To a solution of acetonitrile (4.8 g) in THF (150 mL) was added n-BuLi (67 mmol) at −78° C. Further, methyl butanoate (10 g) was added and the mixture was stirred for one hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyanopentan-2-one (5.5 g) as a colorless oil. A solution of 2-chlorobenzaldehyde (1.9 g), 3-aminopyrazole (1.0 g) and 1-cyanopentan-2-one (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (1.3 g) as colorless crystals.

[0861] MP: 248° C.

[0862] Anal. Calcd. for: C₁₆H₁₅ClN₄:C,64.32;H,5.06;N,18.75.

[0863] Found: C,64.49;H,5.18;N,18.81.

[0864] MS(EI): 298(M⁺).

[0865]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 2.38-2.42(2H,m), 5.36(1H,s), 7.23-7.26(3H,m), 7.32(1H,dd,J=7.3 Hz and 7.4 Hz), 7.42(1H,d,J=7.3 Hz), 9.83(1H,br.s), 12.15(1H,br.s).

Example 95 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(4-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[0866] To a solution of acetonitrile (76 g) in DMSO (100 mL) was added methyl p-anisate (100 g) and the mixture was stirred with heating at 60° C. for one hour. The reaction mixture was allowed to cool, and cold water (500 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give benzoylacetonitrile (60 g) as colorless crystals. A solution of 2-chlorobenzaldehyde (1.7 g), 3-aminopyrazole (1.0 g) and benzoylacetonitrile (1.8 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.63 g) as colorless crystals.

[0867] MP: 124° C.

[0868] Anal. Calcd. for: C₂₀H₁₅ClN₄O 8/5 H₂O:C,61.34;H,4.68;N,14.31.

[0869] Found: C,61.32;H,4.88;N,14.31.

[0870] MS(EI): 362(M⁺).

[0871]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.81(3H,s), 5.48(1H,s), 7.04(2H,d,J=7.3 Hz), 7.26(1H,dd,J=7.3 Hz and 7.4 Hz), 7.32(1H,s), 7.35-7.39(4H,m), 7.45(1H,d,J=7.3 Hz), 9.99(1H,br.s), 12.22(1H,br.s).

Example 96 4-(2-Chlorophenyl)-2,4,7,8-tetrahydrofurano[3,4-b]pyrazolo[4,3-e]pyridin-5-one

[0872] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4-chloroacetoacetate in the same manner as in Example 1.

[0873] MP: >270° C.

[0874] Anal. Calcd. for: C₁₄H₁₀ClN₃O₂ 2/5 H₂O:C,57.02;H,3.69;N,14.25.

[0875] Found: C,57.13;H,3.39;N,14.38.

[0876] MS(FAB): 288(M⁺+1)

[0877]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 4.91(2H,dd,J=5.6 Hz and 26.6 Hz), 5.34(1H,s), 7.15-7.24(3H,m), 7.34(1H,s), 7.41(1H,d,J=6.8 Hz), 10.31(1H,br.s), 12.20(1H,br.s).

[0878] IR(KBr): ν=3167,2966,1722,1637,1608,1510,1026 cm⁻¹.

Example 97 5′-Ethoxycarbonyl-4′,7′-dihydro-6′-propyl-spiro[benzo[b]thiophene-3(2H), 4′-2′H-pyrazolo[3,4-b]pyridine]-5-oxide

[0879] A solution of 2-methylthiobenzaldehyde (62 g), Meldrum's acid.(58.7 g), ethyl 3-ketohexanoate (64.4 g) and ammonium acetate (40 g) in acetic acid (400 mL) was heated under reflux overnight. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure to give colorless crystals (40.2 g). To a solution of dimethylformamide (26.3 g) in chloroform (100 mL) were added, under ice-cooling, phosphorus oxychloride (33.6 mL) and a solution of the obtained colorless crystals (30 g) in chloroform (200 mL), and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (370 g) solution was added and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained crystals in acetone (500 mL) was added diammonium cerium nitrate (42 g) and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give colorless crystals. To a solution of the obtained colorless crystals in tetrahydrofuran (500 mL) was added metachloroperbenzoic acid (12 g) at −78° C. and the mixture was stirred for 30 minutes. An aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give colorless crystals. By recrystallization from ethyl acetate, colorless crystals (15 g) were obtained. To a solution of the obtained colorless crystals in tetrahydrofuran (100 mL) was added lithium diisopropylamide (2.5 eq.) at −78° C. Immediately thereafter, methanol and an aqueous ammonium chloride solution were added. The mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. To a solution of the obtained oil in pyridine (50 mL) was added hydrazine (4.2 g) and the mixture was stirred with heating for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give title compound (0.8 g) as colorless crystals.

[0880] MP: 246° C.

[0881] Anal. Calcd. for: C₁₉H₂₁N₃O₃S: C,61.44;H,5.70;N,11.31.

[0882] Found: C,61.58;H,5.81;N,11.16.

[0883] MS(EI): 371(M⁺).

[0884]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.70(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 2.67-2.76(2H,m), 3.07(1H,d,J=14.9 Hz), 3.64(2H,q,J=7.3 Hz), 4.00(1H,d,J=14.9 Hz), 7.05-7.09(2H,m), 7.40(1H,dd,J=7.3 Hz and 7.4 Hz), 7.50(1H,dd,J=7.3 Hz and 7.4 Hz), 7.81(1H,d,J=7.3 Hz), 9.83(1H,br.s), 12.11(1H,br.s).

Example 98 Ethyl 4,7-dihydro-4-(2-hydroxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0885] A solution of 2-methoxybenzaldehyde (15 g), Meldrum's acid (16 g), ethyl 3-ketohexanoate (17.4 g) and ammonium acetate (9.4 g) in acetic acid (110 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (8.0 g). To a solution of the obtained colorless crystals (5.2 g) in dichloromethane (150 mL) were added ethanedithiol (20 mL) and aluminum chloride (32 g), and the mixture was stirred for 2 hours. After neutralization with 1N aqueous sodium hydroxide solution, the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals (2.0 g). To a solution of dimethylformamide (1.9 g) in chloroform (10 mL) were added phosphorus oxychloride (2.5 mL) and a solution of the obtained crystals in chloroform (20 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (27 g) solution was added and the mixture was stirred for one hour. The mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give a colorless oil (1.4 g). To a solution of the obtained oil in pyridine (10 mL) was added hydrazine (0.7 g), and the mixture was stirred with heating for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (0.2 g) as colorless crystals.

[0886] MP: 177° C.

[0887] Anal. Calcd. for: C₁₈H₂₁N₃ ₃:C,66.04;H,6.47;N,12.84.

[0888] Found: C,65.96;H,6.21;N,12.66.

[0889] MS(EI): 327(M⁺).

[0890]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.80(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.56-1.59(2H,m), 2.70-2.80(2H,m), 3.76(2H,q,J=7.3 Hz), 5.50(1H,s), 7.28-7.33(3H,m), 7.63(1H,dd,J=7.3 Hz and 7.4 Hz), 7.76(1H,d,J=7.3 Hz), 9.64(1H,br.s), 9.68(1H,br.s), 10.12(1H,br.s).

Example 99 Ethyl 4-(2-aminophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0891] To a solution of ethyl 4,7-dihydro-4-(2-nitrophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.68 g) in methanol (30 mL) was added 5% palladium-carbon (500 mg), and the mixture was stirred under 10 atm for 3 hours. After removing palladium-carbon by Celite filtration, the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (120 mg) as colorless crystals.

[0892] MP: 179° C.

[0893] Anal. Calcd. for: C₁₈H₂₂N₄O₂:C,66.24;H,6.79;N,17.17.

[0894] Found: C,65.96;H,6.62;N,17.16.

[0895] MS(EI): 326(M⁺).

[0896]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.82(3H,t,J=7.3 Hz), 0.98(3H,t,J=7.3 Hz), 1.58-1.64(2H,m), 2.72-2.78(2H,m), 3.78(2H,q,J=7.3 Hz), 5.52(1H,s), 6.35-6.38(2H,br.s), 7.28-7.36(3H,m), 7.58(1H,dd,J=7.3 Hz and 7.4 Hz), 7.78(1H,d,J=7.3 Hz), 9.58(1H,br.s), 11.48(1H,br.s).

Example 100 Ethyl 4-(2-ethylphenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0897] The title compound was prepared from 2-ethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0898] MP: 186° C.

[0899] Anal. Calcd. for: C₂₀H₂₅N₃O₂ 1/5 H₂O:C,70.03;H,7.46;N,12.25.

[0900] Found: C,69.91;H,7.53;N,11.98.

[0901] MS(EI): 339(M⁺).

[0902]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.3 Hz), 0.94(3H,t,J=7.3 Hz), 1.24(3H,t,J=7.3 Hz), 1.64(2H,q,J=7.3 Hz), 2.64-2.68(1H,m), 2.77-2.86(3H,m), 3.78(2H,q,J=7.3 Hz), 5.34(1H,s), 6.98-7.01(3H,m), 7.07-7.10(2H,m), 9.34(1H,s), 11.89(1H,s).

Example 101 Ethyl 4,7-dihydro-6-propyl-4-(2-propylphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0903] The title compound was prepared from 2-propylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0904] MP: 197° C.

[0905] Anal. Calcd. for: C₂₁H₂₇N₃O₂:C,71.36;H,7.70;N,11.89.

[0906] Found: C,71.07;H,7.73;N,11.84.

[0907] MS(EI): 353(M⁺).

[0908]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.3 Hz), 0.94-1.00(6H,m), 1.64(2H,q,J=7.3 Hz), 2.68-2.80(4H,m), 3.79(2H,q,J=7.3 Hz), 5.33(1H,s), 6.98-7.06(5H,m), 9.34(1H,s), 11.88(1H,s).

Example 102 Ethyl 4-(2-butylphenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0909] The title compound was prepared from 2-butylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0910] MP: 175° C.

[0911] Anal. Calcd. for: C₂₂H₂₉N₃O₂:C,71.90;H,7.95;N,11.43.

[0912] Found: C,71.50;H,7.94;N,11.36.

[0913] MS(EI): 367(M⁺).

[0914]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.3 Hz), 0.92-0.97(6H,m), 1.40(2H,q,J=7.3 Hz), 1.60-1.66(4H,m), 2.70-2.82(4H,m), 3.80(2H,q,J=7.3 Hz), 5.33(1H,s), 6.97-7.06(5H,m), 9.34(1H,s), 11.88(1H,s).

Example 103 Ethyl 4,7-dihydro-4-(indan-4-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0915] The title compound was prepared from indan-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.

[0916] MP: 181-183° C.

[0917] Anal. Calcd. for: C₂₁H₂₅N₃O₂:C,71.77;H,7.17;N,11.96.

[0918] Found: C,71.66;H,7.14;N,11.88.

[0919] MS(EI): 351(M⁺).

[0920]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90(3H,t,J=7.3 Hz), 0.90(3H,t,J=7.3 Hz), 1.62(2H,m), 1.80-2.10(2H,m), 2.52-3.10(6H,m), 3.77(2H,q,J=7.3 Hz), 5.17(1H,s), 6.81(1H,d,J=6.8 Hz), 6.91-6.96(2H,m), 7.14(1H,s), 9.33(1H,br.s), 11.87(1H,br.s).

Example 104 Ethyl 4,7-dihydro-6-propyl-4-(1,2,3,4-tetrahydronaphthalen-5-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Example 105 Ethyl 4-(benzo[b]furan-7-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Example 106 Ethyl 4-(benzo[b]thiophen-7-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0921] The title compound was prepared from benzo[b]thiophene-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0922] MP: 166° C.

[0923] Anal. Calcd. for: C₂₀H₂₁N₃O₂S 2H₂O: C,59.53;H,6.25;N,10.41.

[0924] Found: C,59.77;H,6.46;N,9.95.

[0925] MS(EI): 367(M⁺).

[0926]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.74(3,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.65-1.69(2H,m), 2.70-2.80(2H,m), 3.71(2H,q,J=7.3 Hz), 5.48(1H,s), 7.11-7.13(2H,m), 7.26(1H,dd,J=7.4 Hz and 7.5 Hz), 7.39(1H,d,J=5.4 Hz), 7.63(1H,d,J=7.3 Hz), 7.68(1H,d,J=5.4 Hz), 9.57(1H,s), 11.91(1H,s).

Example 107 5′-Ethoxycarbonyl-4′,7′-dihydro-6′-propyl-spiro[benzo[b]thiophene-3(2H), 4′-2′H-pyrazolo[3,4-b]pyridine]

[0927] To a solution of 5′-ethoxycarbonyl-4′,7′-dihydro-6′-propyl-spiro[benzo[b]thiophene-3(2H), 4′-2′H-pyrazolo[3,4-b]pyridine]-1-oxide (100 mg) in carbon tetrachloride (20 mL) was added trimethylsilane iodide (0.1 g), and the mixture was stirred with heating for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give the title compound (20 mg) as colorless crystals.

[0928] MP: 147° C.

[0929] Anal. Calcd. for: C₁₉H₂₁N₃O₂S:C,64.20;H,5.95;N,11.82.

[0930] Found: C,64.18;H,6.14;N,11.56.

[0931] MS(EI): 355(M⁺).

[0932]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.73(3H,t,J=7.3 Hz), 0.95(3H,t,J=7.3 Hz), 1.64-1.67(2H,m), 2.56-2.64(2H,m), 3.03(1H,d,J=10.2 Hz), 3.72(2H,q,J=7.3 Hz), 4.03(1H,d,J=10.2 Hz), 6.69(1H,d,J=7.3 Hz), 6.91(1H,dd,J=7.3 Hz and 7.4 Hz), 7.03(1H,dd,J=7.3 Hz and 7.4 Hz), 7.08(1H,s), 7.15(1H,d,J=7.3 Hz), 9.65(1H,br.s), 11.96(1H,br.s).

Example 108 Ethyl 4,7-dihydro-4-methyl-4-phenyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0933] To a solution of 5′-ethoxycarbonyl-4′,7′-dihydro-6′-propyl-spiro[benzo[b]thiophene-3(2H), 4′-2′H-pyrazolo[3,4-b]pyridin]-1-oxide (100 mg) in tetrahydrofuran (10 mL) were added disodium hydrogenphosphate (1.2 g) and methanol (5 mL) under ice-cooling, and 10% sodium amalgam (3.0 g) was added. The mixture was stirred for 5 hours, filtered through Celite and extracted with chloroform. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give the title compound (80 mg) as colorless crystals.

[0934] MP: 207° C.

[0935] Anal. Calcd. for: C₉H₂₃N₃O₂:C,70.13;H,7.12;N,12.91.

[0936] Found: C,69.89;H,7.18;N,12.99.

[0937] MS(EI): 325(M⁺).

[0938]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.71(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.64-1.68(2H,m), 2.28(3H,s), 2.48-2.56(2H,m), 3.71(2H,q,J=7.3 Hz), 6.73-7.01(5H,m), 7.10(1H,s), 9.71(1H,br.s), 11.87(1H,br.s).

Example 109 Ethyl 4,7-dihydro-6-propyl-4-(2,3,5-trichlorophenyl)-pyrazolo[3,4-b]pyridine-5-carboxylate

[0939] The title compound was prepared from 2,3,5-trichlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0940] MP: 218-220° C. (decomposition).

[0941] Anal. Calcd. for: C₁₈H₁₈Cl₃N₃O₂:C,52.13;H,4.37;N,10.13.

[0942] Found: C,51.76;H,4.37;N,10.07.

[0943] MS(EI): 414(M⁺).

[0944]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=6.9 Hz), 0.97(3H,t,J=7.3 Hz), 1.62-1.67(2H,m), 2.65-2.71(1H,m), 2.85-2.92(1H,m), 3.76-3.88(2H,m), 5.62(1H,s), 7.03(1H,d,J=1.6 Hz), 7.33(1H,s), 7.59(1H,d,J=2.4 Hz), 9.69(1H,s), 12.12(1H,s).

Example 110 Ethyl 4,7-dihydro-6-propyl-4-(2,3,4,5-tetrahydrobenzo[b]oxepin-9-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate Example 111 Ethyl 4-(3-chloro-2-methylphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0945] The title compound was prepared from 3-chloro-2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.

[0946] MP: 185° C.

[0947] Anal. Calcd. for: C₁₉H₂₂ClN₃O₂:C,63.42;H,6.16;N,11.68.

[0948] Found: C,63.37;H,6.12;N,11.65.

[0949] MS(EI): 359(M⁺).

[0950]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.3 Hz), 0.95(3H,t,J=7.3 Hz), 1.60-1.66(2H,m), 2.67-2.69(1H,m), 2.74-2.78(1H,m), 3.78(2H,q,J=7.3 Hz), 5.39(1H,s), 6.95(1H,d,J=7.3 Hz), 7.04(1H,dd,J=7.3 Hz and 7.4 Hz), 7.12(1H,d,J=7.3 Hz), 7.24(1H,s), 9.44(1H,br.s), 11.94(1H,br.s).

Example 112 Ethyl 4-(2,1,3-benzothiadiazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0951] The title compound was prepared from 2,1,3-benzothiadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[0952] MP: 180° C.

[0953] Anal. Calcd. for: C₁₈H₁₉N₅O₂S: C,8.52;H,5.18;N,18.96.

[0954] Found: C,58.51;H,5.19;N,18.81.

[0955] MS(EI): 369(M⁺).

[0956]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.62(3H,t,J=7.3 Hz), 1.00(3H,t,J=7.3 Hz), 1.68-1.72(2H,m), 2.76-2.89(2H,m), 3.72(2H,q,J=7.3Hz), 6.02(1H,s), 7.16(1H,s), 7.20(1H,d,J=7.3 Hz), 7.60(1H,dd,J=7.3 Hz and 7.4 Hz), 7.83(1H,d,J=7.3 Hz), 9.55(1H,s), 11.89(1H,s).

Example 113 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0957] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 25.

[0958] MP: 228° C.

[0959] Anal. Calcd. for: C₁₆H₁₅N₅O₃:C,59.07;H,4.65;N,21.53.

[0960] Found: C,58.85;H,4.75;N,21.17.

[0961] MS(EI): 325(M⁺).

[0962]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.75(3H,t,J=7.3 Hz), 2.42(3H,s), 3.79(2H,q,J=7.3 Hz), 5.67(1H,s), 7.14(1H,d,J=6.6 Hz), 7.23(1H,s), 7.49(1H,dd,J=9.0 Hz and 6.6 Hz), 7.78(1H,d,J=9.0 Hz), 9.69(1H,s), 12.02(1H,s).

Example 114 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0963] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.

[0964] MP: 190° C.

[0965] Anal. Calcd. for: C₂₁H₁₇N₅O₃:C,65.11;H,4.42;N,18.08.

[0966] Found: C,64.99;H,4.59;N,18.06.

[0967] MS(EI): 387(M⁺).

[0968]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.54(3H,t,J=7.3 Hz), 3.56(2H,q,J=7.3 Hz), 5.68(1H,s), 7.24(1H,s), 7.26-7.42(6H,m), 7.72(1H,dd,J=7.3 Hz and 7.2 Hz), 7.94(1H,d,J=7.3 Hz), 9.71(1H,s), 12.08(1H,s).

Example 115 Ethyl 4-(2,3-dichlorophenyl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0969] The title compound was prepared from 2,3-dichlorobenzaldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.

[0970] MP: 214° C.

[0971] Anal. Calcd. for: C₂₁H₁₇N₅O₃:C,65.11;H,4.42;N,18.08.

[0972] Found: C,64.85;H,4.48;N,17.92.

[0973] MS(EI): 387(M⁺).

[0974]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.57(3H,t,J=7.3 Hz), 3.52(2H,q,J=7.3 Hz), 5.70(1H,s), 7.30-7.40(9H,m), 9.61(1H,s), 12.12(1H,s).

Example 116 (+)Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0975] The compound described in Example 76 was separated using a semi-preparative column for optical resolution (CHIRALPAK AS, 1.0 cm×25 cm, eluent n-hexane/2-propanol/diethylamine=90/10/0.1, flow rate 2.0 mL/min, UV 254 nm, retention time 40 minutes, DAICEL CHEMICAL INDUSTRIES, LTD.) to give the title compound as colorless crystals.

[0976] MP: 159° C.

[0977] MS(EI): 353(M⁺).

[0978] Specific rotation: [a]_(D)=+260° (EtOH,c=0.5).

Example 117 (−)Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0979] The compound described in Example 76 was separated using a semi-preparative column for optical resolution (CHIRALPAK AS, 1.0 cm×25 cm, eluent n-hexane/2-propanol/diethylamine=90/10/0.1, flow rate 2.0 mL/min, UV 254 nm, retention time 55 minutes, DAICEL CHEMICAL INDUSTRIES, LTD.) to give the title compound as colorless crystals.

[0980] MP: 160° C.

[0981] MS(EI): 353(M⁺).

[0982] Specific rotation: [a]_(D)=−277° (EtOH,c=0.5).

Example 118 4-(2-Bromophenyl)-4,7-dihydro-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[0983] The title compound was prepared from n-butylaldehyde, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[0984] MP: 226° C.

[0985] Anal. Calcd. for: C₁₅H₁₅BrN₄O₂:C,49.60;H,4.16;N,15.43.

[0986] Found: C,49.57;H,4.28;N,14.96.

[0987] MS(EI): 363(M⁺).

[0988]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.02(3H,t,J=7.3 Hz), 1.72-1.76(2H,m), 2.85-3.05(2H,m), 5.89(1H,s), 7.07-7.1(2H,m), 7.25(1H,dd,J=7.5 Hz and 7.4 Hz), 7.47(1H,s), 7.56(1H,d,J=7.3 Hz), 10.84(1H,s), 12.43(1H,s).

Example 119 4,7-Dihydro-4-(2-methoxyphenyl)-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[0989] The title compound was prepared from n-butylaldehyde, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[0990] MP: 223° C.

[0991] Anal. Calcd. for: C₁₆H₁₈N₄O₃:C,61.13;H,5.77;N,17.82.

[0992] Found: C,61.01;H,5.87;N,17.92.

[0993] MS(EI): 314(M⁺).

[0994]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.03(3H,t,J=7.3 Hz), 1.72-1.78(2H,m), 2.82-3.04(2H,m), 3.86(3H,s), 5.76(1H,s), 6.78(1H,dd,J=7.5 Hz and 7.4 Hz), 6.90(1H,d,J=7.3 Hz), 6.95(1H,d,J=7.3 Hz), 7.10(1H,dd,J=7.5 Hz and 7.4 Hz), 7.33(1H,s), 10.68(1H,s), 12.29(1H,s).

Example 120 4,7-Dihydro-4-(2-methylthiophenyl)-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[0995] The title compound was prepared from n-butylaldehyde, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[0996] MP: 211° C.

[0997] Anal. Calcd. for: C₁₆H₁₈N₄O₂S: C,58.16;H,5.49;N,16.96.

[0998] Found: C,57.94;H,5.47;N,16.53.

[0999] MS(EI): 330(M⁺).

[1000]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.02(3H,t,J=7.3z), 1.71-1.76(2H,m), 2.8-3.00(2H,m), 5.89(1H,s), 6.98(1H,d,J=7.3 Hz), 7.03(1H,dd,J=7.5 Hz and 7.4 Hz), 7.13(1H,dd,J=7.5 Hz and 7.4 Hz), 7.28(1H,d,J=7.3 Hz), 7.41(1H,s), 10.74(1H,s), 12.34(1H,s).

Example 121 4,7-Dihydro-5-nitro-4-(2-nitrophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1001] The title compound was prepared from n-butylaldehyde, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1002] MP: 204° C.

[1003] Anal. Calcd. for: C₁₅H₁₅N₅O₄:C,54.71;H,4.59;N,21.27.

[1004] Found: C,54.50;H,4.77;N,21.32.

[1005] MS(EI): 329(M⁺).

[1006]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.01(3H,t,J=7.3 Hz), 1.69-1.74(2H,m), 2.85-2.99(2H,m), 5.67(1H,s), 6.94(1H,d,J=7.3 Hz), 6.98-7.03(2H,m),7.09(1H,d,J=7.3 Hz), 7.38(1H,s), 10.69(1H,s), 12.34(1H,s).

Example 122 4-(2,3-Dichlorophenyl)-4,7-dihydro-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1007] The title compound was prepared from n-butylaldehyde, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1008] MP: 239° C.

[1009] Anal. Calcd. for: C₁₅H₁₄Cl₂N₄O₂:C,51.01;H,4.00;N,15.86.

[1010] Found: C,50.70;H,4.06;N,15.60.

[1011] MS(EI): 353(M⁺).

[1012]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.02(3H,t,J=7.3 Hz), 1.70-1.74(2H,m), 2.89-2.92(1H,m), 2.96-3.02(1H,m), 5.96(1H,s), 7.09(1H,d,J=7.3 Hz), 7.24(1H,dd,J=7.5 Hz and 7.4 Hz), 7.43(1H,d,J=7.3 Hz), 7.49(1H,s), 10.98(1H,s), 12.49(1H,s).

Example 123

[1013] 4,7-Dihydro-4-(naphthalen-1-yl)-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1014] The title compound was prepared from n-butylaldehyde, naphthalen-1-aldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1015] MP: 226° C.

[1016] Anal. Calcd. for: C₁₉H₁₈N₄O₂:C,68.25;H,5.43;N,16.76.

[1017] Found: C,68.29;H,5.20;N,16.67.

[1018] MS(EI): 334(M⁺).

[1019]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.06(3H,t,J=7.3 Hz), 1.76-1.82(2H,m), 2.95-3.06(2H,m), 6.33(1H,s), 7.18-7.22(2H,m), 7.36(1H,dd,J=7.5 Hz and 7.4 Hz), 7.54(1H,dd,J=7.5 Hz and 7.4 Hz), 7.60(1H,dd,J=7.5 Hz and 7.4 Hz), 7.71(1H,d,J=7.3 Hz), 7.92(1H,d,J=7.3 Hz), 8.46(1H,d,J=7.3 Hz), 10.80(1H,s), 12.29(1H,s).

Example 124 4,7-Dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1020] The title compound was prepared from n-butylaldehyde, 3,4-dihydro-2H-benzopyran-8-aldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1021] MP: 234° C.

[1022] Anal. Calcd. for: C₁₃H₂₀N₄O₃:C, 63.52;H,5.92;N,16.46.

[1023] Found: C,63.22;H,5.94;N,16.44.

[1024] MS(EI): 340(M⁺).

[1025]¹H-NMR (400 MHz,DMSO-d₆)6(ppm): 1.02(3H,t,J=7.3 Hz), 1.71-1.77(2H,m), 1.92-1.95(2H,m), 2.69-2.73(2H,m), 2.85-3.02(2H,m), 4.23-4.28(2,m), 5.71(1H,s), 6.61-6.67(2H,m), 6.80(1H,d,J=7.3 Hz), 7.37(1H,s), 10.64(1H,s), 12.28(1H,s).

Example 125 4-(2,3-Dichlorophenyl)-4,7-dihydro-6-methyl-5-nitro-2H-pyrazolo[3,4-b]pyridine

[1026] The title compound was prepared from acetaldehyde, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1027] MP: >270° C.

[1028] Anal. Calcd. for: C₁₃H₁₀Cl₂N₄O₂:C,48.02;H,3.10;N,17.23.

[1029] Found: C,48.05;H,3.12;N,17.24.

[1030] MS(EI): 325(M⁺).

[1031]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.66(3H,s), 5.94(1H,s), 7.13(1H,d,J=7.2 Hz), 7.22(1H,dd,J=7.3 Hz and 7.2 Hz), 7.42(1H,d,J=7.3 Hz), 7.50(1H,s), 10.94(1H,s), 12.49(1H,s).

Example 126 4-(2,3-Dichlorophenyl)-6-ethyl-4,7-dihydro-5-nitro-2H-pyrazolo[3,4-b]pyridine

[1032] The title compound was prepared from propionaldehyde, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1033] MP: 250° C.

[1034] Anal. Calcd. for: C₁₄H₁₂Cl₂N₄O₂:C,49.58;H,3.57;N,16.52.

[1035] Found: C,49.54;H,3.62;N,16.73.

[1036] MS(EI): 339(M⁺).

[1037]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.29(3H,t,J=7.3 Hz), 2.98-3.01(2H,m), 5.94(1H,s), 7.10(1H,d,J=7.3 Hz), 7.24(1H,dd,J=7.3 Hz and 7.2 Hz), 7.42(1H,d,J=7.2 Hz), 7.49(1H,s), 10.93(1H,s), 12.49(1H,s).

Example 127 6-Butyl-4-(2,3-dichlorophenyl)-4,7-dihydro-5-nitro-2H-pyrazolo[3,4-b]pyridine

[1038] The title compound was prepared from pentylaldehyde, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.

[1039] MP: 220° C.

[1040] Anal. Calcd. for: C₁₆H₁₆Cl₂N₄O₂:C,52.33;H,4.39;N,15.26.

[1041] Found: C,52.64;H,4.61;N,14.51.

[1042] MS(EI): 367(M⁺).

[1043]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.41-1.46(2H,m), 1.63-1.68(2H,m), 2.94-3.04(2H,m), 5.95(1H,s), 7.08(1H,d,J=7.2 Hz), 7.23(1H,dd,J=7.3 Hz and 7.2 Hz), 7.42(1H,d,J=7.2 Hz), 7.48(1H,s), 10.97(1H,s), 12.28(1H,s).

Example 128 4-(2-Bromophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1044] The title compound was prepared from methyl butanoate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1045] MP: 237° C.

[1046] Anal. Calcd. for: C₁₆H₁₅BrN₄:C,55.99;H,4.41;N,16.32.

[1047] Found: C,55.97;H,4.45;N,16.40.

[1048] MS(EI): 343(M⁺).

[1049]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2,m), 2.40-2.44(2H,m), 5.35(1H,s), 7.15(1H,dd,J=7.5 Hz and 7.4 Hz), 7.22(1H,d,J=7.3 Hz), 7.27(1H,s), 7.36(1H,dd,J=7.5 Hz and 7.4 Hz), 7.59(1H,d,J=7.3 Hz), 9.84(1H,s), 12.16(1H,s).

Example 129 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1050] The title compound was prepared from methyl butanoate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1051] MP: 203° C.

[1052] Anal. Calcd. for: C₁₇H₁₈N₄O:C,69.37;H,6.16;N,19.03.

[1053] Found: C,69.34;H,6.25;N,19.01.

[1054] MS(EI): 294(M⁺).

[1055]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.96(3H,t,J=7.3 Hz), 1.65-1.70(2H,m), 2.38-2.43(2H,m), 3.83(3H,s), 5.22(1H,s), 6.89(1H,dd,J=7.5 Hz and 7.4 Hz), 6.99(1H,d,J=7.3 Hz), 7.05(1H,d,J=7.3 Hz), 7.15-7.18(2H,m), 9.65(1H,s), 12.02(1H,s).

Example 130 5-Cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1056] The title compound was prepared from methyl butanoate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1057] MP: 216° C.

[1058] Anal. Calcd. for: C₁₇H₁₈N₄S:C,65.78;H,5.84;N,18.05.

[1059] Found: C,65.68;H,5.81;N,17.83.

[1060] MS(EI): 310(M⁺).

[1061]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.96(3H,t,J=7.3 Hz), 1.65-1.70(2H,m), 2.40-2.46(2H,m), 2.48(3H,s), 5.34(1H,s), 7.13-7.21(4H,m), 7.30(1H,d,J=7.3 Hz), 9.75(1H,s), 12.07(1H,s).

Example 131 5-Cyano-4,7-dihydro-4-(2-methylphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1062] The title compound was prepared from methyl butanoate, 2-methylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1063] MP: 230° C.

[1064] Anal. Calcd. for: C₁₇H₁₈N₄:C,73.35;H,6.52;N,20.13.

[1065] Found: C,73.44;H,6.61;N,20.13.

[1066] MS(EI): 278(M⁺).

[1067]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.3 Hz), 1.65-1.67(2H,m), 2.32(3H,s), 2.35-2.41(2H,m), 5.13(1H,s), 7.06-7.16(5H,m), 9.69(1H,s), 12.07(1H,s).

Example 132 5-Cyano-4,7-dihydro-4-(2-nitrophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1068] The title compound was prepared from methyl butanoate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1069] MP: 216° C.

[1070] Anal. Calcd. for: C₁₆H₁₅N₅O₂:C,62.13;H,4.89;N,22.64.

[1071] Found: C,62.16;H,4.93;N,22.57.

[1072] MS(EI): 309(M⁺).

[1073]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.64-1.69(2H,m), 2.36-2.42(2H,m), 5.38(1H,s), 7.27(1H,s), 7.42-7.49(2H,m), 7.70(1H,dd,J=7.5 Hz and 7.4 Hz), 7.89(1H,d,J=7.3 Hz), 9.91(1H,s), 12.21(1H,s).

Example 133 5-Cyano-4-(2-cyanophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1074] The title compound was prepared from methyl butanoate, 2-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1075] MP: 218° C.

[1076] Anal. Calcd. for: C₁₇H₁₅N₅:C,70.57;H,5.23;N,24.21.

[1077] Found: C,70.54;H,5.30;N,24.07.

[1078] MS(EI): 289(M⁺).

[1079]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 2.36-2.40(2H,m), 5.23(1H,s), 7.26(1H,s), 7.38(1H,d,J=7.3 Hz), 7.43(1H,dd,J=7.5 Hz and 7.4 Hz), 7.69(1H,dd,J=7.5 Hz and 7.4 Hz), 7.80(1H,d,J=7.3 Hz), 9.94(1,s), 12.22(1H,s).

Example 134 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1080] The title compound was prepared from methyl butanoate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1081] MP: 242° C.

[1082] Anal. Calcd. for: C₁₆H₁₄Cl₂N₄ 1/5 H₂O:C,57.05;H,4.31;N,16.63.

[1083] Found: C,57.23;H,4.49;N,16.25.

[1084] MS(EI): 333(M⁺).

[1085]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.62-1.68(2H,m), 2.40-2.46(2H,m), 5.44(1H,s), 7.22(1H,d,J=7.3 Hz), 7.30(1H,s), 7.35(1H,dd,J=7.5 Hz and 7.4 Hz), 7.51(1H,d,J=7.3 Hz), 9.89(1H,s), 12.19(1H,s).

Example 135 5-Cyano-4,7-dihydro-4-(naphthalen-1-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1086] The title compound was prepared from methyl butanoate, naphthalene-1-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1087] MP: 263° C.

[1088] Anal. Calcd. for: C₂₀H₁₈N₄:C,76.41;H,5.77;N,17.82.

[1089] Found: C,76.05;H,5.85;N,17.73.

[1090] MS(EI): 314(M⁺).

[1091]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.97(3H,t,J=7.3 Hz), 1.68-1.73(2H,m), 2.44-2.48(2H,m), 5.71(1H,s), 7.04(1H,s), 7.39-7.46(4H,m), 7.81(1H,d,J=7.3 Hz), 7.94(1H,d,J=7.3 Hz), 9.83(1H,s), 12.02(1H,s).

Example 136 5-Cyano-4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1092] The title compound was prepared from methyl butanoate, 3,4-dihydro-2H-benzopyran-8-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1093] MP: 230° C.

[1094] Anal. Calcd. for: C₁₉H₂₀N₄O:C,71.23;H,6.29;N,17.49.

[1095] Found: C,71.20;H,6.48;N,17.55.

[1096] MS(EI): 320(M⁺).

[1097]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 1.92-1.95(2H,m), 2.38-2.43(2H,m), 2.72-2.76(2H,m), 4.16-4.27(2H,m), 5.16(1H,s), 6.74(1H,dd,J=7.5 Hz and 7.4 Hz), 6.83-6.88(2H,m), 7.20(1H,s), 9.62(1H,s), 12.01(1H,s).

Example 137 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1098] The title compound was prepared from methyl butanoate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1099] MP: 194° C.

[1100] Anal. Calcd. for: C₁₆H₁₄N₆O:C,62.73;H,4.61;N,27.44.

[1101] Found: C,62.52;H,4.78;N,27.19.

[1102] MS(EI): 306(M⁺).

[1103]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 2.38-2.43(2H,m), 5.40(1H,s), 7.25(1H,s), 7.40(1H,d,J=7.3 Hz), 7.58(1H,dd,J=7.5 Hz and 7.4 Hz), 7.92(1H,d,J=7.3z), 9.93(1H,s), 12.13(1H,s).

Example 138 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1104] The title compound was prepared from methyl butanoate, 2,1,3-benzothiadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1105] MP: 195° C.

[1106] Anal. Calcd. for: C₁₆H₁₄N₆S:C,59.61;H,4.38;N,26.07.

[1107] Found: C,59.33;H,4.48;N,25.76.

[1108] MS(EI): 322(M⁺).

[1109]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.98(3H,t,J=7.3 Hz), 1.68-1.74(2H,m), 2.45-2.50(2H,m), 5.72(1H,s), 7.19(1H,s), 7.43(1H,d,J=7.3 Hz), 7.72(1H,dd,J=7.5 Hz and 7.4 Hz), 7.97(1H,d,J=7.3 Hz), 9.87(1H,s), 12.06(1H,s).

Example 139 5-Cyano-4,7-dihydro-4-(2-methylbenzoxazol-4-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1110] The title compound was prepared from methyl butanoate, 2-methylbenzoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1111] MP: 208° C.

[1112] Anal. Calcd. for: C₁₈H₁₇N₅O 1/5 H₂O:C,66.94;H,5.43;N,21.68.

[1113] Found: C,66.85;H,5.52;N,22.09.

[1114] MS(EI): 319(M⁺).

[1115]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.97(3H,t,J=7.3 Hz), 1.67-1.72(2H,m), 2.40-2.45(2H,m), 2.63(3H,s), 5.51(1H,s), 7.06(1H,d,J=7.3 Hz), 7.16(1H,s), 7.29(1H,dd,J=7.3 Hz and 7.2 Hz), 7.47(1H,d,J=7.3 Hz), 9.77(1H,s), 12.06(1H,s).

Example 140 R(−) 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1116] To a solution of the compound described in Example 137 (64.5 g) in THF (1000 mL) was added (−)camphorsulfonic acid (49 g) at room temperature and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was recrystallized from acetonitrile twice to give colorless crystals (11 g). To a solution of the obtained colorless crystals in methanol (50 mL) was added water (50 mL). The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure. The residual methanol solution was added dropwise to water (1000 mL) and the crystals were collected by filtration to give the title compound (11 g) as pale-yellow crystals. (CHIRALPAK AS, 0.25 cm×25 cm, eluent n-hexane/2-propanol/diethylamine=80/20/0.1, flow rate 1.5 mL/min, UV 254 nm, retention time 10 minutes, DAICEL CHEMICAL INDUSTRIES, LTD.)

[1117] MP: 170° C.

[1118] MS(EI): 306(M⁺). Specific rotation: [a]_(D)=−80° (EtOH,c=1.0)

Example 141 S(+) 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1119] To a solution of the compound (54 g), which was recovered from the mother liquor obtained in Example 140, in THF (600 mL) was added (+)camphorsulfonic acid (41 g) at room temperature and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was recrystallized from acetonitrile twice to give colorless crystals (12 g). To a solution of the obtained colorless crystals in methanol (50 mL) was added water (50 mL) The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residual methanol solution was added dropwise to water (1000 mL). The crystals were collected by filtration to give the title compound (11 g) as pale-yellow crystals.

[1120] (CHIRALPAK AS, 0.25 cm×25 cm, eluent n-hexane/2-propanol/diethylamine=80/20/0.1, flow rate 1.5 mL/min, UV 254 nm, retention time 13 minutes, DAICEL CHEMICAL INDUSTRIES, LTD.)

[1121] MP: 170° C.

[1122] MS(EI): 306 (M⁺).

[1123] Specific rotation: [a]_(D)=+82° (EtOH,c=1.0).

Example 142 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1124] The title compound was prepared from methyl benzoate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1125] MP: 158° C.

[1126] Anal. Calcd. for: C₁₉H₁₃ClN₄H₂O:C,65.05;H,4.31;N,15.97.

[1127] Found: C,65.35;H,4.19;N,16.21.

[1128] MS(EI): 332 (M⁺).

[1129]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.51(1H,s), 7.25-7.51(8H,m), 7.59-7.61(2H,m), 10.07(1H,s), 12.24(1H,s).

Example 143 5-Cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1130] The title compound was prepared from methyl benzoate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1131] MP: 146° C.

[1132] Anal. Calcd. for: C₂₀H₁₆N₄S 4/5 H₂O:C,66.94;H,4.94;N,15.61.

[1133] Found: C,66.85;H,4.81;N,15.65.

[1134] MS(EI): 344(M⁺).

[1135]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.48(3H,s), 5.48(1H,s), 7.19-7.33(5H,m), 7.48-7.50(3H,m), 7.59-7.61(2H,m), 9.99(1H,s), 12.16(1H,s).

Example 144 5-Cyano-4-(2-cyanophenyl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1136] The title compound was prepared from methyl benzoate, 2-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1137] MP: 148° C.

[1138] Anal. Calcd. for: C₂₀H₁₃N₅ 3/5 H₂O:C,71.89;H,4.28;N,20.96.

[1139] Found: C,71.89;H,4.33;N,20.91.

[1140] MS(EI): 323(M⁺).

[1141]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.38(1H,s), 7.31(1H,s), 7.44-7.59(7H,m), 7.70(1H,dd,J=7.3 Hz and 7.2 Hz), 7.83(1H,d,J=7.3 Hz), 10.21(1H,s), 12.31(1H,s).

Example 145 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1142] The title compound was prepared from methyl benzoate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1143] MP: 162° C.

[1144] Anal. Calcd. for: C₁₉H₁₂Cl₂N₄:C,62.14;H,3.29;N,15.26.

[1145] Found: C,61.57;H,3.93;N,17.19.

[1146] MS(EI): 367(M⁺).

[1147]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.59(1H,s), 7.37-7.42(3H,m), 7.48-7.55(4H,m), 7.59-7.62(2H,m), 10.14(1H,s), 12.28(1H,s).

Example 146 5-Cyano-4,7-dihydro-4-(naphthalen-1-yl)-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1148] The title compound was prepared from methyl benzoate, naphthalene-1-benzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1149] MP: 174° C.

[1150] Anal. Calcd. for: C₂₃H₁₆N₄:C,79.29;H,4.63;N,16.08.

[1151] Found: C,79.50;H,4.85;N,16.58.

[1152] MS(EI): 348(M⁺).

[1153]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.87(1H,s), 7.12(1H,s), 7.50-7.63(9H,m), 7.82(1H,d,J=7.3 Hz), 7.96(1H,d,J=7.3 Hz), 8.34(1H,d,J=7.3 Hz), 10.09(1H,s), 12.12(1H,s).

Example 147 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1154] The title compound was prepared from methyl benzoate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1155] MP: >270° C.

[1156] Anal. Calcd. for: C₂₀H₁₂BrN₅:C,59.72;H,3.01;N,17.41.

[1157] Found: C,59.53;H,3.17;N,17.30.

[1158] MS(EI): 402(M⁺).

[1159]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.63(1H,s), 7.39(1H,s), 7.49-7.51(3H,m), 7.60-7.63(3H,m), 7.75(1H,d,J=7.3 Hz), 7.85(1H,d,J=7.3 Hz), 10.21(1H,s), 12.33(1H,s).

Example 148 5-Cyano-4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1160] The title compound was prepared from methyl benzoate, 3,4-dihydro-2H-benzopyran-8-benzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1161] MP: 255° C.

[1162] Anal. Calcd. for: C₂₂H₁₈N₄O:C,74.56;H,5.12;N,15.81.

[1163] Found: C,74.27;H,5.11;N,15.82.

[1164] MS(EI): 354(M⁺).

[1165]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.94-1.97(2H,m), 2.75-2.78(2H,m), 4.20-4.30(2H,m), 5.30(1H,s), 6.80(1H,dd,J=7.3 Hz and 7.2 Hz), 6.91(1H,d,J=7.3 Hz), 7.02(1H,d,J=7.3 Hz), 7.28(1H,s), 7.49-7.51(3H,m), 7.60-7.63(2H,m), 9.88(1H,s), 12.11(1H,s).

Example 149 5-Cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1166] The title compound was prepared from methyl benzoate, 2,3-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1167] MP: 165° C.

[1168] Anal. Calcd. for: C₁₉H₁₂F₂N₄ 3/5 H₂O:C,66.12;H,3.86;N,16.23.

[1169] Found: C,65.87;H,3.81;N,16.46.

[1170] MS(EI): 334(M⁺).

[1171]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.40(1H,s), 7.16-7.38(4H,m), 7.48-7.50(3H,m), 7.57-7.59(2H,m), 10.11(1H,s), 12.30(1H,s).

Example 150 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1172] The title compound was prepared from methyl benzoate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1173] MP: 206° C.

[1174] Anal. Calcd. for: C₂₀H₁₆N₄O:C,73.15;H,4.91;N,17.06.

[1175] Found: C,73.23;H,5.14;N,17.19.

[1176] MS(EI): 328(M⁺).

[1177]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.86(3H,s), 5.36(1H,s), 6.94(1H,dd,J=7.3 Hz and 7.2 Hz), 7.02(1H,d,J=7.3 Hz), 7.19-7.25(3H,m), 7.48-7.51(3H,m), 7.60-7.63(2H,m), 9.91(1H,s), 12.12(1H,s)

Example 151 5-Cyano-4,7-dihydro-4,6-bis-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1178] The title compound was prepared from methyl o-anisate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1179] MP: 220° C.

[1180] Anal. Calcd. for: C₂₁H₁₈N₄O₂:C,70.38;H,5.06;N,15.63.

[1181] Found: C,69.97;H,5.13;N,16.15.

[1182] MS(EI): 358(M⁺).

[1183]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.86(3H,s), 3.88(3H,s), 5.32(1H,s), 6.95-7.06(3H,m), 7.14-7.25(3H,m), 7.37(1H,d,J=7.3 Hz), 7.45(1H,dd,J=7.3 Hz and 7.2 Hz), 9.74(1H,s), 12.05(1H,s).

Example 152 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(3-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1184] The title compound was prepared from methyl m-anisate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1185] MP: 192° C.

[1186] Anal. Calcd. for: C₂₁H₁₈N₄O₂:C,70.38;H,5.06;N,15.63.

[1187] Found: C,69.97;H,5.09;N,15.54.

[1188] MS(EI): 358(M⁺).

[1189]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.81(3H,s), 3.86(3H,s), 5.35(1H,s), 6.95(1H,dd,J=7.3 Hz and 7.2 Hz), 7.01(1H,d,J=7.3 Hz), 7.07(1H,d,J=7.3 Hz), 7.14(1H,s), 7.18-7.23(5H,m), 7.41(1H,dd,J=7.3 Hz and 7.2 Hz), 9.88(1H,s), 12.12(1H,s).

Example 153 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1190] The title compound was prepared from methyl p-anisate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1191] MP: 149° C.

[1192] Anal. Calcd. for: C₂₁H₁₈N₄O₂ 1/2 H₂O:C,68.65;H,5.21;N,15.25.

[1193] Found: C,68.67;H,4.99;N,15.35.

[1194] MS(EI): 358(M⁺).

[1195]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.81(3H,s), 3.86(3H,s), 5.33(1H,s), 6.94(1H,dd,J=7.3 Hz and 7.2 Hz), 7.01-7.05(3H,m), 7.18-7.24(3H,m), 7.56(2H,d,J=7.2 Hz), 9.82(1H,s), 12.10(1H,s).

Example 154 5-Cyano-4,7-dihydro-4-(2-nitrophenyl)-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1196] The title compound was prepared from methyl benzoate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1197] MP: 221° C.

[1198] Anal. Calcd. for: C₁₉H₁₃N₅O₂:C,66.47;H,3.82;N,20.40.

[1199] Found: C,66.48;H,4.08;N,20.41.

[1200] MS(EI): 343(M⁺).

[1201]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 7.34(1H,s), 7.49-7.52(4H,m), 7.59-7.64(3H,m), 7.74(1H,dd,J=7.3 Hz and 7.2 Hz), 7.91(1H,d,J=7.3 Hz), 10.16(1H,s), 12.30(1H,s).

Example 155 5-Cyano-4,7-dihydro-6-(2-methoxyphenyl)-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[1202] The title compound was prepared from methyl o-anisate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1203] MP: 207° C.

[1204] Anal. Calcd. for: C₂₀H₁₅N₅O₃:C,64.34;H,4.05;N,18.76.

[1205] Found: C,64.03;H,4.21;N,18.68.

[1206] MS(EI): 373(M⁺).

[1207]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.85(3H,s), 5.50(1H,s), 7.03(1H,dd,J=7.3 Hz and 7.2 Hz), 7.14(1H,d,J=7.3 Hz), 7.33(1H,s), 7.37(1H,d,J=7.3 Hz), 7.44-7.52(2H,m), 7.74-7.80(2H,m), 7.92(1H,d,J=7.3 Hz), 10.02(1H,s), 12.25(1H,s).

Example 156 5-Cyano-4,7-dihydro-6-(3-methoxyphenyl)-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[1208] The title compound was prepared from methyl m-anisate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1209] MP: 220° C.

[1210] Anal. Calcd. for: C₂₀H₁₅N₅O₃:C,64.34;H,4.05;N,18.76.

[1211] Found: C,63.92;H,4.14;N,18.74.

[1212] MS(EI): 373(M⁺).

[1213]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 381(3H,s), 5.53(1H,s), 7.07(1H,d,J=7.3 Hz), 7.14-7.18(2H,m), 7.33(1H,s), 7.40(1H,dd,J=7.3 Hz and 7.2 Hz), 7.50(1H,dd,J=7.3 Hz and 7.2 Hz), 7.63(1H,d,J=7.3 Hz), 7.74(1H,dd,J=7.3 Hz 7.2 Hz), 7.91(1H,d,J=7.3 Hz), 10.13(1H,s), 12.30(1H,s).

Example 157 5-Cyano-4,7-dihydro-6-(4-methoxyphenyl)-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[1214] The title compound was prepared from methyl p-anisate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1215] MP: 215° C.

[1216] Anal. Calcd. for: C₂₀H₁₅N₅O₃:C,64.34;H,4.05;N,18.76.

[1217] Found: C,64.13;H,4.12;N,18.69.

[1218] MS(EI): 373(M⁺).

[1219]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.81(3H,s), 5.51(1H,s), 7.03(2H,d,J=7.3 Hz), 7.33(1H,s), 7.47-7.55(3H,m), 7.61(1H,d), 7.74(1H,dd,J=7.3 Hz and 7.2 Hz), 7.91(1H,d,J=7.3 Hz), 10.07(1H,s), 12.28(1H,s).

Example 158 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1220] The title compound was prepared from methyl benzoate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1221] MP: 231° C.

[1222] Anal. Calcd. for: C₁₉H₁₂N₆O:C,67.05;H,3.55;N,24.69.

[1223] Found: C,66.76;H,3.90;N,24.71.

[1224] MS(EI): 340(M⁺).

[1225]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.55(1H,s), 7.33(1H,s), 7.50-7.64(7H,m), 7.95(1H,d,J=7.3 Hz), 10.20(1H,s), 12.23(1H,s).

Example 159 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1226] The title compound was prepared from methyl o-anisate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1227] MP: 180° C.

[1228] Anal. Calcd. for: C₂₀H₁₄N₆O₂:C,64.86;H,3.81;N,22.69.

[1229] Found: C,64.11;H,3.98;N,22.34.

[1230] MS(EI): 370(M⁺).

[1231]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.84(3H,s), 5.56(1H,s), 7.03(1H,dd,J=7.3 Hz and 7.2 Hz), 7.14(1H,d,J=6.8 Hz), 7.33-7.35(2H,m), 7.45(1H,dd,J=7.3 Hz and 7.2 Hz), 7.54(1H,d,J=7.3 Hz), 7.65(1H,dd,J=8.8 Hz and 6.8 Hz), 7.94(1H,d,J=8.8 Hz), 10.04(1H,s), 12.18(1H,s)

Example 160 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(3-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1232] The title compound was prepared from methyl m-anisate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1233] MP: 198° C.

[1234] Anal. Calcd. for: C₂₀H₁₄N₆O₂ 4/5 H₂O:C,62.43;H,4.09;N,21.84.

[1235] Found: C,62.60;H,3.99;N,22.15.

[1236] MS(EI): 370(M⁺).

[1237]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.80(3H,s), 5.55(1H,s), 7.06-7.17(3H,m), 7.33(1H,s), 7.40(1H,dd,J=7.3 Hz), 7.52(1H,d,J=6.6 Hz), 7.62(1H,dd,J=8.8 Hz and 6.8 Hz), 7.95(1H,d,J=6.8 Hz), 10.18(1H,s), 12.24(1H,s).

Example 161 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1238] The title compound was prepared from methyl p-anisate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1239] MP: 244° C.

[1240] Anal. Calcd. for: C₂₀H₁₄N₆O₂:C,64.86;H,3.81;N,22.69.

[1241] Found: C,64.77;H,3.91;N,22.49.

[1242] MS(EI): 370(M⁺).

[1243]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.80(3H,s), 5.53(1H,s), 7.02(2H,d,J=7.3 Hz), 7.32(1H,s), 7.50-7.53(3H,m), 7.61(1H,dd,J=8.8 Hz and 6.8 Hz), 7.94(1H,d,J=8.8 Hz), 10.11(1H,s), 12.21(1H,s)

Example 162 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1244] The title compound was prepared from methyl benzoate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1245] MP: 258° C.

[1246] MS(EI): 356(M⁺).

[1247]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.85(1H,s), 7.27(1H,s), 7.51-7.52(3H,m), 7.61-7.67(3H,m), 7.76(1H,dd,J=8.8 Hz and 6.8 Hz), 8.00(1H,d,J=8.8 Hz), 10.13(1H,s), 12.16(1H,s).

Example 163 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1248] The title compound was prepared from methyl o-anisate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1249] MP: 231° C.

[1250] Anal. Calcd. for: C₂₀H₁₄N₆OS 3/10 H₂O:C,61.30;H,3.76;N,21.45.

[1251] Found: C,61.24;H,3.74;N,22.09.

[1252] MS(EI): 386(M⁺).

[1253]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.89(3H,s), 5.85(1H,s), 706(1H,dd,J=7.6 Hz and 7.3 Hz), 7.17(1H,d,J=8.3 Hz), 7.28(1H,s), 7.43-7.49(2H,m), 7.69(1H,d,J=6.8 Hz), 7.80(1H,dd,J=8.8 Hz and 6.8 Hz), 7.99(1H,d,J=8.8 Hz), 9.97(1H,s), 12.11(1H,s).

Example 164 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(3-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1254] The title compound was prepared from methyl m-anisate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1255] MP: 220° C.

[1256] Anal. Calcd. for: C₂₀H₁₄N₆OS: C,62.16;H,3.65;N,21.75.

[1257] Found: C,61.98;H,3.70;N,21.66.

[1258] MS(EI): 386(M⁺).

[1259]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.82(3H,s), 5.85(1H,s), 7.08(1H,d,J=8.3 Hz), 7.19(1H,s), 7.23-7.27(2H,m), 7.42(1H,dd,J=7.8 Hz and 7.2 Hz), 7.61(1H,d,J=6.6 Hz), 7.75(1H,dd,J=8.8 Hz and 6.8 Hz), 7.99(1H,d,J=8.1 Hz), 10.10(1H,s), 12.16(1H,s).

Example 165 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1260] The title compound was prepared from methyl p-anisate, 2,1,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1261] MP: 238° C.

[1262] MS(EI): 386(M⁺).

[1263]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.81(3H,s), 5.83(1H,s), 7.04(2H,d,J=8.8 Hz), 7.26(1H,s), 7.73-7.77(3H,m), 7.75(1H,dd,J=8.8 Hz and 6.8 Hz), 7.99(1H,d,J=8.8 Hz), 10.04(1H,s), 12.14(1H,s).

Example 166 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[1264] The title compound was prepared from methyl isonicotinate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1265] MP: 236° C.

[1266] MS(EI): 341(M⁺).

[1267]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.58(1H,s), 7.35(1H,s), 7.54-7.64(4H,m), 7.96(1H,d,J=8.1 Hz), 8.72(2H,d,J=5.9 Hz), 10.40(1H,s), 12.29(1H,s).

Example 167 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[1268] The title compound was prepared from methyl nicotinate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1269] MP: 216° C.

[1270] Anal. Calcd. for: C₁₈H₁₁N₇O 1/5 H₂O:C,62.68;H,3.33;N,28.43.

[1271] Found: C,62.73;H,3.43;N,28.30.

[1272] MS(EI): 341(M⁺).

[1273]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.59(1H,s), 7.35(1H,s), 7.52-7.63(3H,m), 7.95-8.00(2H,m), 8.69(1H,d,J=4.9 Hz), 8.76(1H,s), 10.39(1H,s), 12.28(1H,s).

Example 168 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1274] The title compound was prepared from methyl picolinate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1275] MP: 188° C.

[1276] MS(EI): 341(M⁺).

[1277]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.59(1H,s), 7.34(1H,s), 7.51-7.53(2H,m), 7.63(1H,dd,J=9.0 Hz and 6.6 Hz), 7.75(1H,d,J=6.6 Hz), 7.95-7.97(2H,m), 8.69(1H,d,J=5.4 Hz), 10.20(1H,s), 12.26(1H,s).

Example 169 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(naphthalen-1-yl)-2H-pyrazolo[3,4-b]pyridine

[1278] The title compound was prepared from methyl 1-naphthoate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1279] MP: 213° C.

[1280] Anal. Calcd. for: C₂₃H₁₄N₆O:C,70.76;H,3.61;N,21.53.

[1281] Found: C,70.33;H,3.74;N,21.23.

[1282] MS(EI): 390(M⁺).

[1283]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.65(1H,s), 7.35-7.66(7H,m), 7.96-8.21(4H,m), 10.35(1H,s), 12.23(1H,s).

Example 170 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-(furan-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1284] The title compound was prepared from methyl furan-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1285] MP: 241° C.

[1286] Anal. Calcd. for: C₁₇H₁₀N₆O₂:C,61.82;H,3.05;N,25.44.

[1287] Found: C,61.72;H,3.19;N,25.34.

[1288] MS(EI): 330(M⁺).

[1289]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 6.69(1H,s), 7.22(1H,d,J=3.4 Hz), 7.32(1H,s), 7.48(1H,d,J=6.3 Hz), 7.61(1H,dd,J=9.0 Hz and 6.3 Hz), 7.89(1H,s), 7.94(1H,d,J=9.0 Hz), 10.17(1H,s), 12.26(1H,s).

Example 171 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1290] The title compound was prepared from methyl thiophene-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1291] MP: 230° C.

[1292] Anal. Calcd. for: C₁₇H₁₀N₆OS: C, 58.95;H,2.91;N,24.26.

[1293] Found: C,58.71;H,3.08;N,24.03.

[1294] MS(EI): 346(M⁺).

[1295]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 7.17(1H,dd,J=4.9 Hz and 4.8 Hz), 7.33(1H,s), 7.49(1H,d,J=6.6 Hz), 7.58-7.64(2H,m), 7.77(1H,d,J=4.9 Hz), 7.95(1H,d,J=9.0 Hz), 10.21(1H,s), 12.27(1H,s).

Example 172 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(naphthalen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1296] The title compound was prepared from methyl 2-naphthoate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1297] MP: 228° C.

[1298] Anal. Calcd. for: C₂₃H₁₄N₆O:C,70.76;H,3.61;N,21.53.

[1299] Found: C,70.66;H,3.81;N,20.94.

[1300] MS(EI): 390(M⁺).

[1301]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.48(1H,s), 7.24(1H,s), 7.44-7.55(5H,m), 7.85-7.92(4H,m), 8.05(1H,s), 10.21(1H,s), 12.14(1H,s).

Example 173 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-(furan-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1302] The title compound was prepared from methyl furan-3-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1303] MP: 237° C.

[1304] Anal. Calcd. for: C₁₇H₁₀N₆O₂:C,61.82;H,3.05;N,25.44.

[1305] Found: C,61.59;H,3.27;N,25.01.

[1306] MS(EI): 330(M⁺).

[1307]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.52(1H,s), 6.93(1H,d,J=1.0 Hz), 7.31(1H,s), 7.48(1H,d,J=6.6 Hz), 7.60(1H,dd,J=9.0 Hz and 6.6 Hz), 7.80(1H,dd,J=1.0 Hz), 7.94(1H,d,J=9.0 Hz), 8.24(1H,s), 10.07(1H,s), 12.25(1H,s).

Example 174 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(thiophen-3-yl)-2H-pyrazolo[3,4-b]pyridine

[1308] The title compound was prepared from methyl thiophene-3-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1309] MP: 242° C.

[1310] Anal. Calcd. for: C₁₇H₁₀N₆OS: C,58.95;H,2.91;N,24.26.

[1311] Found: C,58.52;H,3.15;N,23.92.

[1312] MS(EI): 346(M⁺).

[1313]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 7.32(1H,s), 7.42(1H,d,J=5.1 Hz), 7.50(1H,d,J=6.6 Hz), 7.61-7.66(2H,m), 7.94(1H,d,J=9.0 Hz), 8.00(1H,s), 10.13(1H,s), 12.24(1H,s).

Example 175 6-(Benzo[b]furan-2-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1314] The title compound was prepared from methyl benzo[b]furan-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1315] MP: >270° C.

[1316] Anal. Calcd. for: C₂₁H₁₂N₆O₂:C,66.31;H,3.18;N,22.09.

[1317] Found: C,66.26;H,3.34;N,21.53.

[1318] MS(EI): 380(M⁺).

[1319]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.62(1H,s), 7.31-7.36(2H,m), 7.45(1H,dd,J=9.0 Hz and 6.7 Hz), 7.53(1H,d,J=6.7 Hz), 7.61-7.65(3H,m), 7.77(1H,d,J=7.3 Hz), 7.96(1H,d,J=9.0 Hz), 10.44(1H,s), 12.33(1H,s).

Example 176 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine

[1320] The title compound was prepared from ethyl acetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1321] MP: 212° C.

[1322] Anal. Calcd. for: C₁₄H₁₀N₆O 3/5 H₂O:C,58.17;H,3.91;N,29.07.

[1323] Found: C,58.45;H,4.08;N,28.61.

[1324] MS(EI): 278(M⁺).

[1325]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.14(3H,s), 5.40(1H,s), 7.25(1H,s), 7.40(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.98(1H,s), 12.13(1H,s).

Example 177 4-(2,1,3-Benzoxadiazol-4-yl)-6-butyl-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1326] The title compound was prepared from methyl pentanoate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1327] MP: 200° C.

[1328] Anal. Calcd. for: C₁₇H₁₆N₆O:C,63.74;H,5.03;N,26.23.

[1329] Found: C,63.85;H,5.01;N,26.26.

[1330] MS(EI): 320(M⁺).

[1331]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 1.30-1.39(2H,m), 1.57-1.65(2H,m), 2.06-2.40(2H,m), 5.39(1H,s), 7.25(1H,s), 7.39(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.94(1H,s), 12.13(1H,s).

Example 178 Ethyl 4-(2-chloro-3-methylphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1332] A suspension of 2-chloro-m-xylene (15 ml), N-bromosuccinimide (23.3 g) and benzoyl peroxide (200 mg) in carbon tetrachloride (150 ml) was heated under reflux for 6 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-bromomethyl-1-chloro-6-methylbenzene (16.0 g) as a colorless oil. 2-Bromomethyl-1-chloro-6-methylbenzene (25.4 g) and hexamethylenetetramine (32.4 g) were dissolved in acetic acid-water (1:1, 10 ml) and the mixture was heated under reflux for 5 hours. To the reaction mixture was added concentrated hydrochloric acid (40 ml) and the mixture was heated under reflux for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-3-methylbenzaldehyde (19.4 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chloro-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1333] MP: 198-200° C.

[1334] Anal. Calcd. for: C₁₉H₂₂ClN₃O₂:C,63.42;H,6.16;N,11.68.

[1335] Found: C,63.19;H,6.14;N,11.71.

[1336] MS(EI): 359(M⁺).

[1337]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.65(2H,m), 2.33(3H,s), 2.68-2.71(1H,m), 2.79-2.84(1H,m), 3.72-3.82(2H,m), 5.63(1H,s), 6.93-6.96(1H,m), 7.05-7.07(2H,m), 7.24(1H,s), 9.46(1H,s), 11.94(1H,s).

Example 179 Ethyl 4-(2-chloro-3-nitrophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1338] To a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in THF (50 ml) was added borane-tetrahydrofuran complex (1M THF solution, 30 ml) under ice-cooling and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a pale-yellow solid (3.7 g). The obtained pale-yellow solid (1.6.g) and manganese dioxide (1.7 g) were heated under reflux in toluene for 4.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (4:1)) to give 2-chloro-3-nitrobenzaldehyde (1.3 g) as a pale-yellow solid. Subsequently, the title compound was prepared from 2-chloro-3-nitrobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1339] MS(EI): 390(M⁺).

[1340]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=6.8 Hz), 0.97(3H,t,J=7.3 Hz), 1.64-1.68(2H,m), 2.70-2.85(2H,m), 3.73-386(2H,m), 5.67(1H,s), 7.31(1H,s), 7.39-7.47(2H,m), 7.73(1H,dd,J=1.5,7.8 Hz), 9.67(1H,s), 12.10(1H,s).

Example 180 Ethyl 4-(2-chloro-3-cyanophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1341] To a solution of 2-chloro-3-methylbenzaldehyde (19.4 g) in ethanol (45 ml) was added an aqueous hydroxylamine hydrochloride (9.7 g) solution (12 ml), and an aqueous sodium hydroxide (6.9 g) solution (10 ml) was added. The mixture was stirred at room temperature for 1.5 hours. Water (500 ml) was added and the precipitated crystals were collected by filtration. The obtained white crystals (16.1 g) were dissolved in acetic anhydride (50 ml) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 2-cyano-6-methylchlorobenzene (10.9 g) as a white solid. A suspension of 2-cyano-6-methylchlorobenzene (10.9 g), N-bromosuccinimide (12.8 g) and benzoyl peroxide (523 mg) in carbon tetrachloride (100 ml) was heated under reflux for 3.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (20:1)) to give 2-chloro-3-cyanobenzaldehyde (12.8 g) as a colorless oil. Subsequently, the title compound was prepared from 2-chloro-3-cyanobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1342] MP: 213-215° C.

[1343] Anal. Calcd. for: C₁₉H₁₉ClN₄O₂:C,61.54;H,5.16;N,15.11.

[1344] Found: C,61.25;H,5.36;N,14.71.

[1345] MS(EI): 370(M⁺).

[1346]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=6.9 Hz), 0.96(3H,t,J=7.3 Hz), 1.65(2H,m), 2.70-2.80(2H,m), 3.73-3.81(2H,m), 5.63(1H,s), 7.31(1H,s), 7.42-7.44(2H,m), 7.72(1H,dd,J=3.0, 6.4 Hz), 9.65(1H,s), 12.08(1H,s).

[1347] IR(KBr): ν=3344,3292,2985,2954,2242,1652 cm⁻¹.

Example 181 Ethyl 4-(2,3-dibromophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1348] A suspension of 2-bromo-3-nitrotoluene (5.0 g), iron (3.9 g) and ammonium chloride (3.7 g) in ethanol (50 ml)—water (17 ml) was heated under reflux for 2 hours. The insoluble matter was filtered off. To the filtrate was added ethyl acetate (100 ml) and the mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give a pale-yellow oil (4.8 g). The obtained pale-yellow oil (4.8 g) was dissolved in 47% hydrobromic acid (50 ml). Under ice-cooling, an aqueous sodium nitrite (1.6 g) solution (18 ml) was added and the mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was added dropwise to a solution of cuprous bromide (2.0 g) in 47% hydrobromic acid (20 ml) over 30 minutes and the mixture was stirred at 60° C. for 4.5 hours. To the reaction mixture was added water (100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (9:1)) to give 2,3-dibromotoluene (2.6 g) as a brown oil. A suspension of 2,3-dibromotoluene (2.6 g), N-bromosuccinimide (1.85 g) and benzoyl peroxide (50 mg) in carbon tetrachloride (30 ml) was heated under reflux for 2 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane) to give a colorless oil (1.1 g). To a solution of the obtained colorless oil (1.1 g) in dimethyl sulfoxide (8.6 ml)—methylene chloride (2 ml) was added trimethylamine-N-oxide (1.0 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 ml) and the mixture was extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2,3-dibromobenzaldehyde (0.5 g) as a brown oil. Then the title compound was prepared from 2,3-dibromobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1349] MP: 180-183° C. (decomposition).

[1350] MS(EI): 469(M⁺).

[1351]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.65(2H,m), 2.70-2.80(2H,m), 3.72-3.83(2H,m), 5.67(1H,s), 7.07(1H,d,J=5.8 Hz), 7.18(1H,dd,J=5.8,7.8 Hz), 7.48(1H,d,J=7.8 Hz), 9.57(1H,s), 12.02(1H,s)

[1352] IR(KBr): ν=3344,3292,2985,2954,2242,1652 cm⁻¹.

Example 182 Ethyl 4-(2-bromo-3-nitrophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 1/2 H₂O

[1353] A suspension of 2-bromo-3-nitrotoluene (5.1 g), N-bromosuccinimide (4.2 g) and benzoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g). The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid-water (1:1, 16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-bromo-3-nitrobenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-bromo-3-nitrobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1354] MP: 213-215° C.

[1355] Anal. Calcd. for: C₁₈H₁₉BrN₄O₄ 1/2 H₂O:C,48.66; H,4.54;N,12.61.

[1356] Found: C,48.34;H,4.20;N,13.04.

[1357] MS(EI): 435(M⁺).

[1358]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 2.77-2.81(2H,m), 3.72-3.85(2H,m), 5.68(1H,s), 7.33-7.36(2H,m), 7.47(1H,dd,J=7.8,7.8 Hz), 7.66(1H,d,J=7.8 Hz), 9.67(1H,s), 12.09(1H,s).

Example 183 Ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1359] The title compound was prepared from 2-bromo-m-xylene, 3-aminopyrazole and ethyl 3-ketohexanoate in the. same manner as in Example 180.

[1360] MP: 210-212° C. (decomposition)

[1361] Anal. Calcd. for: C₁₉H₁₉BrN₄O₂:C,54.95;H,4.61;N,13.49.

[1362] Found: C,54.98;H,4.94;N,13.11.

[1363] MS(EI): 415(M⁺).

[1364]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=6.8 Hz), 0.97(3H,t,J=7.3 Hz), 1.62-1.68(2H,m), 2.75-2.80(2H,m), 3.72-3.83(2H,m), 5.63(1H,s), 7.32(1H,s), 7.39-7.48(2H,m), 7.68(1H,dd,J=1.9,7.3 Hz), 9.65(1H,s), 12.07(1H,s).

Example 184 4-(2-Chloro-3-cyanophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1365] The title compound was prepared from methyl butanoate, 2-chloro-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1366] MP: >250° C.

[1367] Anal. Calcd. for: C₁₇H₁₄Cl₃N₅:C,63.06;H,4.36; N,21.63.

[1368] Found: C,63.10;H,4.42;N,21.61.

[1369] MS(EI): 323(M⁺).

[1370]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.61-1.71(2H,m), 2.35-2.49(2H,m), 5.47(1H,s), 7.32(1H,s), 7.52-7.59(2H,m), 7.87(1H,dd,J=2.0,7.3 Hz), 9.95(1H,s), 12.24(1H,s).

Example 185 4-(2-Chloro-3-nitrophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1371] The title compound was prepared from methyl butanoate, 2-chloro-3-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1372] MP: 234-235° C.

[1373] Anal. Calcd. for: C₁₆H₁₄ClN₅O₂:C,55.90;H,4.10;N,20.37.

[1374] Found: C,55.93;H,4.34;N,20.72.

[1375] MS(EI): 343(M⁺).

[1376]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.64-20 1.69(2H,m), 2.37-2.45(2H,m), 5.52(1H,s), 7.34(1H,s), 7.54-7.60(2H,m), 7.89(1H,dd,J=2.0,6.9 Hz), 9.97(1H,s), 12.25(1H,s).

Example 186 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine 1/5 H₂O

[1377] The title compound was prepared from methyl butanoate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1378] MP: 275-279° C. (decomposition)

[1379] Anal. Calcd. for: C₁₇H₁₄BrN₅ 1/5 H₂O:C,55.05;H,3.89;N,18.88.

[1380] Found: C,54.98;H,3.91;N,18.81.

[1381] MS(EI): 368(M⁺).

[1382]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.64-1.69(2H,m), 2.38-2.43(2H,m), 5.47(1H,s), 7.33(1H,s), 7.54-7.60(2H,m), 7.83(1H,dd,J=2.0,7.4 Hz), 9.95(1H,s), 12.24(1H,s).

Example 187 (+)Ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1383] To a solution of the compound (1.94 g) described in Example 73 in acetonitrile (15 ml) was added (−)-10-camphorsulfonic acid (1.23 g) at 50° C. and the mixture was stirred under ice-cooling for 30 minutes. The precipitated crystals were collected by filtration and recrystallized (ethanol-ethyl acetate (2:1), 30 ml) to give white crystals (0.81 g). The obtained white crystals were suspended in water and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate and the extract was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a colorless transparent oil. The obtained colorless transparent oil was crystallized from ethyl acetate to give the title compound (470 mg) as white crystals.

[1384] MP: 159-161° C.

[1385] Anal. Calcd. for: C₂₁H₂₅N₃O₃:C,68.64;H,6.86;N,11.44.

[1386] Found: C,68.37;H,6.86;N,11.26.

[1387] Specific rotation: [α]_(D)=+200° (EtOH,c=0.5).

[1388] MS(EI): 367(M⁺).

[1389]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=6.8 Hz), 0.98(3H,t,J=7.3 Hz), 1.60-1.70(2H,m), 1.90-2.00(2H,m), 2.67-2.82(4H,m), 3.81(2H,m), 4.25(2H,m), 5.42(1H,s), 6.62(1H,dd,J=7.4,7.8 Hz), 6.72-6.76(2H,m), 7.18(1H,s), 9.26(1H,s), 11.81(1H,s).

Example 188 (−)Ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1390] The filtrate obtained by filtering off the (−)-10-camphorsulfonate salt in Example 187 was concentrated under reduced pressure and suspended in water. To the suspension was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give white crystals (780 mg). By the same process as in Example 187 using the obtained white crystals and (+)-10-camphorsulfonic acid, the title compound (150 mg) was obtained as white crystals.

[1391] MP: 160-161° C.

[1392] Anal. Calcd. for: C₂₁H₂₅N₃O₃:C,68.64;H,6.86; N,11.44.

[1393] Found: C,68.49;H,6.81;N,11.42.

[1394] Specific rotation: [a]_(D)=−202° (EtOH,c=0.5)

[1395] MS(EI): 367(M⁺).

[1396]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=6.8 Hz), 0.98(3H,t,J=7.3 Hz), 1.60-1.70(2H,m), 1.90-2.00(2H,m), 2.67-2.82(4H,m), 3.81(2H,m), 4.25(2H,m), 5.42(1H,s), 6.62(1H,dd, J=7.4,7.8 Hz), 6.72-6.76(2H,m), 7.18(1H,s), 9.26(1H,s), 11.81(1H,s).

Example 189 4-(2-Bromo-3-nitrophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1397] The title compound was prepared from methyl butanoate, 2-bromo-3-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1398] MP: 250-255° C. (decomposition).

[1399] Anal. Calcd. for: C₁₆H₁₄BrN₅O₂:C,49.50;H,3.63;N,18.04.

[1400] Found: C,49.37;H,3.76;N,18.02.

[1401] MS(EI): 388(M⁺).

[1402]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.6 Hz), 1.64-1.70(2H,m), 2.39-2.44(2H,m), 5.53(1H,s), 7.34(1H,s), 7.49(1H,d,J=7.8 Hz), 7.60(1H,dd,J=7.8,8.0 Hz), 7.82(1H,d,J=8.0 Hz), 9.97(1H,s), 12.25(1H,s).

Example 190 Ethyl 4,7-dihydro-4-(2-methoxy-3-methylphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1403] A suspension of 2,6-dimethylphenol (19.5 g), iodomethane (31 ml) and potassium carbonate (33.2 g) in dimethylformamide (200 ml) was stirred at 60° C. for 10 hours. The reaction mixture was poured into water (300 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-methoxy-m-xylene (12 g) as a colorless oil. A suspension of 2-methoxy-m-xylene (5.1 g), N-bromosuccinimide (4.2 g) and bezoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g). The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid-water (1:1,16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-methoxy-3-methylbenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-methoxy-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1404] MP: 220-222° C.

[1405] Anal. Calcd. for: C₂₀H₂₅N₃O₃:C,67.58;H,7.09; N,11.82.

[1406] Found: C,67.47;H,7.02;N,11.91.

[1407] MS(EI): 355(M⁺).

[1408]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.0 Hz), 0.97(3H,t,J=7.3 Hz), 1.60-1.70(2H,m), 2.23(3H,s), 2.66-2.85(2H,m), 3.81(3H,s), 3.81-3.85(2H,m), 5.43(1H,s), 6.82-6.91(3H,m), 7.13(1H,s), 9.31(1H,s), 11.82(1H,s).

Example 191 Ethyl 4-(3-cyano-2-methoxyphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1409] The title compound was prepared from 2-methoxy-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 180.

[1410] MP: 220-222° C.

[1411] Anal. Calcd. for: C₂₀H₂₂N₄O₃:C,65.56;H,6.05; N,15.29.

[1412] Found: C,65.20;H,6.10;N,15.23.

[1413] MS(EI): 366(M⁺).

[1414]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.1 Hz), 0.96(3H,t,J=7.3 Hz), 1.60-1.70(2H,m), 2.70-2.80(2H,m), 3.75-3.90(2H,m), 4.02(3H,s), 5.46(1H,s), 7.14-7.19(2H,m), 7.32(1H,d,J=6.1 Hz), 7.53(1H,d,J=7.8 Hz), 9.51(1H,s), 11.97(1H,s).

Example 192 5-Cyano-6-ethyl-4,7-dihydro-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[1415] The title compound was prepared from methyl propionate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1416] MP: 228-230° C. (decomposition)

[1417] Anal. Calcd. for: C₁₅H₁₃N₅O₂:C,61.01;H,4.44;N,23.72.

[1418] Found: C,60.72;H,4.51;N,23.78.

[1419] MS(EI): 295(M⁺).

[1420]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,t,J=7.4 Hz), 2.42-2.49(2H,m), 5.37(1H,s), 7.27(1H,s), 7.43-7.49(2H,m), 7.70(1H,dd,J=7.6,8.0 Hz), 7.89(1H,d,J=8.0 Hz), 9.94(1H,s), 12.21(1H,s).

Example 193 5-Cyano-4-(2,3-dichlorophenyl)-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1421] The title compound was prepared from methyl propionate, 2,3-dichlorobenzaldehyde, 3-aminopyrazole and 1-cyanobutan-2-one in the same manner as in Example 94.

[1422] MP: >300° C.

[1423] Anal. Calcd. for: C₁₅H₁₂Cl₂N₄:C,56.44;H,3.79;N,17.55.

[1424] Found: C,56.33;H,3.86;N,17.67.

[1425] MS(EI): 319(M⁺).

[1426]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,t,J=7.6 Hz), 2.38-2.49(2H,m), 5.43(1H,s), 7.23(1H,d,J=6.8 Hz), 7.31-7.37(2H,m), 7.51(1H,dd,J=1.7,8.1 Hz), 9.92(1H,s), 12.19(1H,s).

Example 194 5-Cyano-6-ethyl-4,7-dihydro-4-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1427] The title compound was prepared from methyl propionate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1428] MP: 230-232° C.

[1429] Anal. Calcd. for: C₁₆H₁₆N₄O:C,68.55;H,5.75;N,19.99.

[1430] Found: C,68.16;H,5.97;N,20.39.

[1431] MS(EI): 280(M⁺).

[1432]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.22(3H,t,J=7.6 Hz), 2.42-2.49(2H,m), 3.84(3H,s), 5.21(1H,s), 6.86-6.91(1H,m), 6.99(1H,d,J=8.3 Hz), 7.05(1H,d,J=7.6 Hz), 7.15-7.19(2H,m), 9.68(1H,s), 12.02(1H,s).

Example 195 4-(2-Chloro-3-cyanophenyl)-5-cyano-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1433] The title compound was prepared from methyl propionate, 2-chloro-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1434] MP: >300° C.

[1435] Anal. Calcd. for: C₁₆H₁₂ClN₅:C,62.04;H,3.90;N,22.61.

[1436] Found: C,61.74;H,4.14;N,22.93.

[1437] MS(EI): 309(M⁺).

[1438]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,t,J=7.6 Hz), 2.42-2.49(2H,m), 5.45(1H,s), 7.33(1H,s), 7.52-7.60(2H,m), 7.87(1H,dd,J=2.0,7.3 Hz), 9.97(1H,s), 12.23(1H,s).

Example 196 4-(2,1,3-Benzoxazol-4-yl)-5-cyano-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1439] The title compound was prepared from methyl propionate, 2,1,3-benzoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1440] MP: 206-208° C. (decomposition).

[1441] Anal. Calcd. for: C₁₅H₁₂N₆O:C,61.64;H,4.14;N,28.75.

[1442] Found: C,61.43;H,4.41;N,28.85.

[1443] MS(EI): 292(M⁺).

[1444]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.20(3H,t,J=7.6 Hz), 2.40-2.50(2H,m), 5.40(1H,s), 7.26(1H,s), 7.40(1H,d,J=6.6 Hz), 7.58(1H,dd,J=6.6,9.0 Hz), 7.92(1H,d,J=9.0 Hz), 9.97(1H,s), 12.14(1H,s).

Example 197 4-(2-Chlorophenyl)-5-cyano-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1445] The title compound was prepared from methyl propionate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1446] MP: >300° C.

[1447] Anal. Calcd. for: C₁₅H₁₃ClN₄:C,63.27;H,4.60; N,19.68.

[1448] Found: C,63.14;H,4.69;N,19.67.

[1449] MS(EI): 284(M⁺).

[1450]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,t,J=7.6 Hz), 2.42-2.49(2H,m), 5.35(1H,s), 7.22-7.26(3H,m), 7.30-7.34(1H,m), 7.42(1H,d,J=7.8 Hz), 9.85(1H,s), 12.15(1H,s).

Example 198 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1451] The title compound was prepared from methyl propionate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1452] MP: >300° C.

[1453] Anal. Calcd. for: C₁₆H₁₂BrN₅:C,54.25;H,3.41; N,19.77.

[1454] Found: C,54.13;H,3.56;N,19.98.

[1455] MS(EI): 354(M⁺).

[1456]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,t,J=7.6 Hz), 2.43(2H,m), 5.46(1H,s), 7.33(1H,s), 7.56-7.60(2H,m), 7.82-7.84(1H,m), 9.98(1H,s), 12.24(1H,s).

Example 199 4-(2-Bromophenyl)-5-cyano-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1457] The title compound was prepared from methyl propionate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1458] MP: 250-253° C. (decomposition)

[1459] Anal. Calcd. for: C₁₅H₁₃BrN₄:C,54.73; H,3.98; N,17.02.

[1460] Found: C,54.28;H,3.96;N,16.94.

[1461] MS(EI): 329(M⁺).

[1462]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,t,J=7.6 Hz), 2.42-2.45(2H,m), 5.34(1H,s), 7.16(1H,dd,J=7.5,7.6 Hz), 7.22(1H,d,J=6.6 Hz), 7.27(1H,s), 7.36(1H,dd,J=6.3,7.3 Hz), 7.59(1H,d,J=6.8 Hz), 9.86(1H,s), 12.15(1H,s).

Example 200 Ethyl 4-(2-chlorophenyl)-6-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 1/4 hydrate

[1463] A solution of 1,1′-carbonylbis-1H-imidazole (22.5 g), ethanol (8.1 ml) and toluene (100 ml) was stirred at room temperature for 1.5 hours. To the reaction mixture was added ice-water (100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated-aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give a colorless oil (19.3 g). A solution of the obtained residue (19.3 g) and pyruvic aldehyde dimethyl acetal (11.1 ml) in toluene (50 ml) was added dropwise to a suspension of sodium hydride (8.44 g) in toluene (250 ml) under reflux with heating over 15 minutes, and the mixture was heated under reflux for 1.5 hours. To the reaction mixture was added a 10% aqueous citric acid solution (610 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give ethyl 4,4-dimethoxy-3-oxobutanoate (15.1 g) as a colorless oil. Subsequently, ethyl 4-(2-chlorophenyl)-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate was obtained as a yellow solid from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4,4-dimethoxy-2-oxobutanoate in the same manner as in Example 1. To a solution of ethyl 4-(2-chlorophenyl)-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (463 mg) in tetrahydrofuran (5 ml) was added 1N hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give ethyl 4-(2-chlorophenyl)-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (290 mg) as a yellow solid. A solution of ethyl 4-(2-chlorophenyl)-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (290 mg) and hydroxylamine-O-sulfonic acid (128.5 mg) in water (10 ml)-ethanol (10 ml) was stirred at 80° C. for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) and crystallized from ethanol-ethyl acetate to give the title compound (53 mg) as yellow crystals.

[1464] MP: 275-278° C. (decomposition).

[1465] Anal. Calcd. for: C₁₆H₁₃ClN₄O₂ 1/4 H₂O:C,57.66;H,4.08;N,16.81.

[1466] Found: C,57.54;H,4.06;N,16.66.

[1467] MS(EI): 328(M⁺).

[1468]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.1 Hz), 3.91(2H,m), 5.67(1H,s), 7.15-7.19(2H,m), 7.25(1H,dd,J=7.3,8.3 Hz), 7.33(1H,s), 7.39(1H,d,J=8.3 Hz), 10.81(1H,s), 12.34(1H,s).

Example 201 4-(2-Chloro-3-trifluoromethylphenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1469] The title compound was prepared from methyl butanoate, 2-chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1470] MP: >250° C.

[1471] Anal. Calcd. for: C₁₇H₁₄ClF₃N₄:C,55.67;H,3.85;N,15.28.

[1472] Found: C, 55.81;H,3.97;N,15.44.

[1473] MS(EI): 366(M⁺).

[1474]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 2.40-2.43(2H,m), 5.55(1H,s), 7.31(1H,s), 7.54-7.56(2H,m), 7.74(1H,dd,J=3.6,5.6 Hz), 9.93(1H,s), 12.22(1H,s).

Example 202

[1475] 4-(2-Chloro-3-trifluoromethylphenyl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo [3,4-b]pyridine

[1476] The title compound was prepared from benzoic acid, 2-chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1477] MP: >250° C.

[1478] Anal. Calcd. for: C₂₀H₁₂ClF₃N₄:C,59.94;H,3.02;N,13.98.

[1479] Found: C,59.74;H,3.18;N,13.95.

[1480] MS(EI): 400(M⁺).

[1481]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 570(1H,s), 7.39(1H,s), 7.49-7.51(3H,m), 7.57-7.62(3H,m), 7.75-7.79(2H,m), 10.18(1H,s), 12.31(1H,s).

Example 203 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[1482] The title compound was prepared from methyl isobutyrate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1483] MP: >250° C.

[1484] Anal. Calcd. for: C₁₆H₁₅ClN₄:C, 64.32;H,5.06;N,18.75.

[1485] Found: C,64.18;H,5.12;N,18.84.

[1486] MS(EI): 298(M⁺).

[1487]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.23(3H,d,J=6.8 Hz), 1.27(3H,d,J=6.8 Hz), 3.06(1H,m), 5.34(1H,s), 7.22-7.26(3H,m), 7.30-7.34(1H,m), 7.42(1H,d,J=7.1 Hz), 9.63(1H,s), 12.16(1H,s).

Example 204 Ethyl 1-tert-butoxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1488] To a solution of the compound (1.2 g) described in Example 27 and dimethylaminopyridine (128 mg) in THF (40 ml) was added di-.tert-butyldicarbonate (830 mg) and the mixture was stirred at room temperature for one day. The solvent was evaporated under reduced pressure and the title compound (102 mg) was obtained as colorless crystals by silica gel column chromatography (eluent:hexane-ethyl acetate (3:1)).

[1489] MP: 112-116° C.

[1490] Anal. Calcd. for: C₂₃H₂₈ClN₃O₄:C,61.95;H,6.33;N,9.42.

[1491] Found: C,61.84;H,6.33;N,9.34.

[1492] MS(EI): 445(M⁺).

[1493]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=6.9 Hz), 0.98(3H,t,J=7.3 Hz), 1.56(9H,s), 1.62-1.72(2H,m), 2.80-2.92(2H,m), 3.85(2H,q,J=6.9 Hz), 5.56(1H,s), 7.14-7.17(2H,m), 7.23(1H,dd,J=7.3 and 7.8 Hz), 7.30(1H,s), 7.39(1H,d,J=7.4 Hz), 8.75(1H,s).

Example 205 Ethyl 2-tert-butoxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1494] Through the column of silica gel column chromatography used in Example 204 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound (300 mg) was obtained as colorless crystals.

[1495] MP: 144-147° C.

[1496] Anal. Calcd. for: C₂₃H₂₈ClN₃O₄:C,61.95;H,6.33;N,9.42.

[1497] Found: C,61.93;H,6.35;N,9.40.

[1498] MS(EI): 445(M⁺).

[1499]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=6.9 Hz), 0.97(3H,t,J=7.3 Hz), 1.49(9H,s), 1.63-1.69(2H,m), 2.66-2.85(2H,m), 3.80(2H,q,J=6.9 Hz), 5.57(1H,s), 7.10-7.15(1H,m), 7.17(1H,ddd,J=1.5, 7.3 and 7.8 Hz), 7.23(1H,dd,J=6.4 and 7.3 Hz), 7.41(1H,d,J=7.2 Hz), 7.67(1H,s), 10.01(1H,s).

Example 206 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-1-methoxycarbonyl-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1500] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and methyl chloroformate in the same manner as in Example 204.

[1501] MS(EI): 403(M⁺).

[1502] IR(KBr): ν=3422,1736,1699,1531,1450,1232,1086 cm⁻¹.

[1503]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.1 Hz), 0.97(3H,t,J=7.3 Hz), 1.60-1.66(2H,m), 2.86-2.89(2H,m), 3.83(2H,q,J=7.1 Hz), 3.94(3H,s), 5.55(1H,s), 7.13-7.38(4H,m), 7.35(1H,s), 8.67(1H,s)

Example 207 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-2-methoxycarbonyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1504] Through the column of silica gel column chromatography used in Example 206 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.

[1505] MP: 141-143° C.

[1506] MS(EI): 403(M⁺).

[1507] IR(KBr): ν=3290,1774,1695,1633,1597,1523,1444,1364,1307,1209 cm⁻¹.

[1508]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.1 Hz), 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 2.71-2.85(2H,m), 3.78(2H,q,J=7.1 Hz), 3.85(1H,s), 5.57(1H,s), 7.10-7.24(3H,m), 7.42(1H,d,J=1.4 Hz), 7.72(1H,s), 9.94(1H,s).

Example 208 Ethyl 1-benzyloxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1509] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and benzyl chloroformate in the same manner as in Example 204.

[1510] MP: 80° C.

[1511] Anal. Calcd. for: C₂₆H₂₆ClN₃O₄:C,65.07;H,5.46;N,8.75.

[1512] Found: C,65.24;H,5.71;N,8.50.

[1513] MS(EI): 479(M⁺).

[1514] IR(KBr): ν=3344,1745,1701,1527,1451,1226,1084,1060 cm⁻¹.

[1515]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.0 Hz), 0.94(3H,t,J=7.3 Hz), 1.56-1.62(2H,m), 2.81-2.88(2H,m), 3.82(2H,q,J=7.0 Hz), 5.41(2H,s), 5.55(1H,s), 7.13-7.24(3H,m), 7.36(1H,s), 7.37(6H,m), 8.62(1H,s).

Example 209 Ethyl 2-benzyloxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1516] Further elution using the column of silica gel column chromatography in Example 208 and hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.

[1517] MS(EI): 479(M⁺).

[1518] IR(KBr): ν=3294,1759,1697,1601,1383,1363,1300,1201 cm⁻¹.

[1519]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.0 Hz), 0.95(3H,t,J=7.3 Hz), 1.61-1.67(2H,m), 2.72-2.82(2H,m), 3.79(2H,q,J=7.0 Hz), 5.30(2H,s), 5.56(1H,s), 7.09-7.41(9H,m), 7.73(1H,s), 9.95(1H,s).

Example 210 Ethyl 1-benzoyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1520] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and benzoyl chloride in the same manner as in Example 204.

[1521] MP: 115° C.

[1522] Anal. Calcd. for: C₂₅H₂₄ClN₃O₃:C,66.74;H,5.38;N,9.34.

[1523] Found: C,66.58;H,5.41;N,9.28.

[1524] MS(EI): 449(M⁺).

[1525] IR(KBr): ν=3414,1680,1641,1516,1095 cm⁻¹.

[1526]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90(3H,t,J=6.3 Hz), 1.00(3H,t,J=7.3 Hz), 1.65-1.71(2H,m), 2.90-2.93(2H,m), 3.85(2H,q,J=7.3 Hz), 5.63(1H,s), 7.16-7.22(2H,m), 7.29(1H,d,J=7.3 Hz), 7.40(1H,d,J=7.8 Hz), 7.46(1H,s), 7.50-7.54(2H,m), 7.65(1H,dd,J=6.3 and 7.8 Hz), 7.98(1H,d,J=6.3 Hz), 9.10(1H,s).

Example 211 Ethyl 2-benzoyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1527] Through the column of silica gel column chromatography used in Example 210 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.

[1528] MP: 119-121° C.

[1529] Anal. Calcd. for: C₂₅H₂₄ClN₃O₃:C,66.74;H,5.38;N,9.34.

[1530] Found: C,66.58;H,5.43;N,9.30.

[1531] MS(EI): 479(M⁺).

[1532] IR(KBr): ν=3406,1670,1628,1601,1481,1348,1084 cm⁻¹.

[1533]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=6.8 Hz), 0.97(3H,t,J=7.3 Hz), 1.65-1.67(2H,m), 2.74-2.83(2H,m), 3.82(2H,q,J=7.3 Hz), 5.65(1H,s), 7.13-7.26(3H,m), 7.44(1H,d,J=7.8 Hz), 7.47-7.51(2H,m), 7.60(1H,dd,J=7.3 and 7.3 Hz), 7.91(2H,d,J=7.8), 8.00(1H,s), 10.06(1H,s).

Example 212 Ethyl 1-benzylcarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1534] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenylacetyl chloride in the same manner as in Example 204.

[1535]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=6.8 Hz), 0.94(3H,t,J=7.3 Hz), 1.60-1.61(2H,m), 2.84-2.86(2H,m), 3.82(2H,q,J=6.8 Hz), 4.47(2H,s), 5.59(1H,s), 7.20-9.44(10H,m), 8.90(1H,s).

Example 213 Ethyl 2-benzylcarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1536] Through the column of silica gel column chromatography used in Example 212 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.

[1537] MS(EI): 463(M⁺).

[1538] IR(KBr): ν=3308,1699,1628,1630,1599,1523 cm⁻¹.

[1539]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=6.8 Hz), 0.98(3H,t,J=7.3 Hz), 1.65-1.71(2H,m), 2.77-2.84(2H,m), 3.83(2H,q,J=6.8 Hz), 4.25(2H,s), 5.60(1H,s), 7.11-7.31(8H,m), 7.41(1H,d,J=7.8 Hz), 7.84(1H,s), 10.30(1H,s).

Example 214

[1540] Ethyl 4-(2-chlorophenyl)-4,7-dihydro-1-phenylcarbamoyl-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1541] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenyl isocyanate in the same manner as in Example 204.

[1542] MS(EI): 464(M⁺).

[1543] IR(KBr): ν=3310,1699,1597,1518,1448,1369,1228,1194,1093 cm⁻¹.

[1544]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.98(3H,t,J=7.1 Hz), 0.97(3H,t,J=7.3 Hz), 1.96(2H,m), 2.87(2H,m), 3.83(2H,q,J=7.1 Hz), 5.61(1H,s), 7.11-7.69(8H,m), 7.67(2H,d,J=7.8 Hz), 8.86(1H,s), 10.31(1H,s).

Example 215 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-2-phenylcarbamoyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1545] Through the column of silica gel column chromatography used in Example 214 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.

[1546] MP: 145-147° C.

[1547] Anal. Calcd. for: C₂₅H₂₅ClN₄O₃:C,64.58;H,5.42;N,12.05.

[1548] Found: C,64.10;H,5.41;N,12.30.

[1549] MS(EI): 464(M⁺).

[1550] IR(KBr): ν=3341,1697,1653,1630,1597,1520,1367,1197,1093 cm⁻¹.

[1551]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.0 Hz), 0.97(3H,t,J=7.3 Hz), 1.68(2H,m), 2.80-2.92(2H,m), 3.82(2H,q,J=7.0 Hz), 5.62(1H,s), 7.10-7.20(3H,m), 7.22(1H,dd,J=7.1 and 7.1 Hz), 7.31-7.33(2H,m), 7.41(1H,d,J=7.1 Hz), 7.58-7.60(2H,m), 7.85(1H,s), 9.67(1H,s), 9.83(1H,s).

Example 216 Ethyl 1-benzylcarbamoyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1552] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and benzyl isocyanate in the same manner as in Example 204.

[1553] MS(EI): 478(M⁺).

[1554] IR(KBr): ν=3402,1699,1637,1525,1226,1091 cm⁻¹.

[1555]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.0 Hz), 0.96(3H,t,J=7.3 Hz), 1.61-1.63(2H,m), 2.83(2H,m), 3.82(2H,q,J=7.0 Hz), 4.37(2H,d), 5.58(1H,s), 7.11-7.31(9H,m), 7.38(1H,d,J=7.8 Hz), 8.74(1H,s), 9.01(1H,s).

Example 217 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-1-phenoxycarbonyl-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1556] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenyl chloroformate in the same manner as in Example 204.

[1557] MS(EI): 465(M⁺).

[1558] IR(KBr): ν=3339,1728,1633,1525,1371,1302,1224,1091 cm⁻¹.

[1559]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83(3H,t,J=7.1 Hz), 0.96(3H,t,J=7.3 Hz), 1.70(2H,m), 2.94(2H,m), 3.82(2H,q,J=7.1 Hz), 5.62(1H,s), 7.12-7.53(9H,m), 8.26(1H,s), 9.30(1H,s).

Example 218 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-2-phenoxycarbonyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1560] Through the column of silica gel column chromatography used in Example 217 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.

[1561] MP: 156-157° C.

[1562] Anal. Calcd. for: C₂₅H₂₄ClN₃O₄:C,64.44;H,5.19;N,9.02.

[1563] Found: C,64.42;H,5.31;N,9.04.

[1564] MS(EI): 465(M⁺).

[1565] IR(KBr): ν=3325,1765,1685,1597,1525,1373,1205,1099 cm⁻¹.

[1566]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.1 Hz), 1.00(3H,t,J=7.3 Hz), 1.67-1.69(2H,m), 2.76-2.85(2H,m), 3.82(2H,q,J=7.1 Hz), 5.61(1H,s), 7.15(1H,dd,J=1.7 and 6.8 Hz), 7.15(1H,dd,J=1.7 and 6.8 Hz), 7.17(1H,dd,J=2.0 and 7.6 Hz), 7.24(1H,dd,J=1.3 and 7.4 Hz), 7.27-7.31(3H,m), 7.41-7.45(3H,m), 7.89(1H,s), 10.01(1H,s).

Example 219 Ethyl 4-(2-chlorophenyl)-l-ethoxycarbonyl-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1567] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and ethyl chloroformate in the same manner as in Example 204.

[1568] MP: 88-89° C.

[1569] Anal. Calcd. for: C₂₁H₂₄ClN₃O₄:C,60.36;H,5.79;N,10.06.

[1570] Found: C,60.24;H,5.72;N,10.05.

[1571] MS(EI): 417(M⁺).

[1572] IR(KBr): ν=3422,1734,1705,1647,1591,1531,1228,1086,1062 cm⁻¹.

[1573]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.1 Hz), 0.96(3H,t,J=7.3 Hz), 1.31(3H,t,J=7.1 Hz), 1.61-1.66(2H,m), 2.83-2.92(2H,m), 3.83(2H,q,J=7.1 Hz), 4.41(2H,q,J=7.1 Hz), 5.55(1H,s), 7.13-7.16(2H,m), 7.25(1H,dd,J=7.0 and 7.6 Hz), 7.34(1H,s), 7.38(1H,d,J=7.6 Hz), 8.65(1H,s).

Example 220 Ethyl 4-(2-chlorophenyl)-2-ethoxycarbonyl-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1574] Through the column of silica gel column chromatography used in Example 219 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.

[1575] MS(EI): 417(M⁺).

[1576] IR(KBr): ν=3325,1765,1685,1631,1597,1525,1373,1205,1099 cm⁻¹.

[1577]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.1 Hz), 0.97(3H,t,J=7.3 Hz), 1.26(3H,t,J=7.0 Hz), 1.63-1.69(2H,m), 2.74-2.81(2H,m), 3.81(2H,q,J=7.1 Hz), 4.29(2H,q,J=7.0 Hz), 5.57(1H,s), 7.12(1H,dd,J=6.3 and 7.5 Hz), 7.17(1H,d,J=7.8 Hz), 7.23(1H,dd,J=6.3 and 7.4 Hz), 7.40(1H,d,J=7.8 Hz), 7.71(1H,s), 9.96(1H,s).

Example 221 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-1-propoxycarbonyl-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1578] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and propyl chloroformate in the same manner as in Example 204.

[1579] MP: 66-68° C.

[1580] MS(EI): 431(M⁺).

[1581] IR(KBr): ν=3356,1738,1695,1527,1282,1084 cm⁻¹.

[1582]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.0 Hz), 0.92(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.62-1.67(2H,m), 1.70-1.75(2H,m), 2.85-2.92(2H,m), 3.83(2H,q,J=7.0 Hz), 4.32(2H,t,J=6.5 Hz), 5.57(1H,s), 7.14-7.18(2H,m), 7.26(1H,dd,J=6.3 and 7.6 Hz), 7.35(1H,s), 7.39(1H,d,J=7.8 Hz) 9.10(1H,s).

Example 222 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-2-propoxycarbonyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1583] Through the column of silica gel column chromatography used in Example 221 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.

[1584] MP: 59° C.

[1585] Anal. Calcd. for: C₂₂H₂₆ClN₃O₄:C,61.18;H,6.07;N,9.73.

[1586] Found: C,60.81;H,5.98;N,9.74.

[1587] MS(EI): 431(M⁺).

[1588] IR(KBr): ν=3296,1761,1697,1633,1599,1523,1365,1218,1089 cm⁻¹.

[1589]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.1 Hz), 0.89(3H,t,J=7.5 Hz), 0.97(3H,t,J=7.3 Hz), 1.63-1.69(4H,m), 2.74-2.81(2H,m), 3.81(2H,q,J=7.1 Hz), 4.21(2H,t,J=6.6 Hz), 5.58(1H,s), 7.12(1H,dd,J=1.8 and 7.6 Hz), 7.17(1H,ddd,J=1.9, 7.3 and 7.6 Hz), 7.22(1H,ddd,J=1.2, 7.3 and 7.6 Hz), 7.41(1H,dd,J=1.2 and 7.8 Hz), 7.72(1H,s), 9.99(1H,s).

Example 223 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-2-isobutylyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1590] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and isobutyryl chloride in the same manner as in Example 204.

[1591]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.0 Hz), 0.96(3H,t,J=7.3 Hz), 1.10(3H,d,J=6.9 Hz), 1.14(3H,d,J=6.8 Hz), 1.64-1.70(2H,m), 2.75-2.83(2H,m), 3.53(1H,q,J=7.0 Hz), 3.83(2H,t,J=6.9 Hz), 5.59(1H,s), 7.12(1H,s), 7.16(1H,dd,J=5.8 and 7.8 Hz), 7.24(1H,dd,J=6.3 and 7.5 Hz), 7.41(1H,s), 7.81(1H,s), 10.05(1H,s).

Example 224 Ethyl 1-acetyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1592] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and acetyl chloride in the same manner as in Example 204.

[1593] MP: 75-76° C.

[1594] Anal. Calcd. for: C₂₀H₂₂ClN₃O₃:C,61.93;H,5.72;N,10.83.

[1595] Found: C,61.77;H,5.78;N,10.90.

[1596] MS(EI): 387(M⁺).

[1597]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 0.97(3H,t,J=7.3 Hz), 1.60-1.66(2H,m), 2.66(3H,s), 2.85-2.90(2H,m), 3.81(2H,q,J=7.3 Hz), 5.57(1H,s), 7.14-7.18(2H,m), 7.26(1H,dd,J=7.3 and 7.6 Hz), 7.38(1H,s), 7.39(1H,d,J=8.1 Hz), 8.90(1H,s).

Example 225 Ethyl 2-acetyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1598] Through the column of silica gel column chromatography used in Example 224 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.

[1599] MS(EI): 387(M⁺).

[1600] IR(KBr): ν=3306,1699,1633,1601,1523,1371,1197,1086 cm⁻¹.

[1601]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.0 Hz), 0.96(3H,t,J=7.3 Hz), 1.66(2H,m), 2.44(3H,s), 2.65-2.85(2H,m), 3.80(2H,q,J=7.0 Hz), 5.58(1H,s), 7.09-7.22(3H,m), 7.40(1H,d,J=7.9 Hz), 7.80(1H,s), 10.0(1H,s).

Example 226 Ethyl 1-butoxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1602] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and butyl chloroformate in the same manner as in Example 204.

[1603] MS(EI): 445(M⁺).

[1604]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.3 Hz), 0.88(3H,t,J=7.1 Hz), 1.33-1.38(2H,m), 1.60-1.69(4H,m), 2.85-2.87(2H,m), 3.82(2H,q,J=7.3 Hz), 4.36(2H,t,J=6.5 Hz), 5.55(1H,s), 7.13-7.17(2H,m), 7.25(1H,dd,J=6.4 and 6.5 Hz), 7.34(1H,s), 7.37(1H,d,J=7.5 Hz), 8.61(1H,s).

Example 227 Ethyl 2-butoxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1605] Through the column of silica gel column chromatography used in Example 226 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.

[1606] MS(EI): 445(M⁺).

[1607]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.3 Hz), 0.87(3H,t,J=7.3 Hz), 0.96(3H,t,J=7.3 Hz), 1.31-1.32(2H,m), 1.61(4H,m), 2.73-2.80(2H,m), 3.80(2H,q,J=7.3 Hz), 4.24(2H,t,J=6.5 Hz), 5.57(1H,s), 7.09-7.22(3H,m), 7.39(1H,d,J=7.8 Hz), 7.70(1H,s), 9.98(1H,s).

Example 228 Ethyl 4-(2-chlorophenyl)-1-cinnamoyl-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1608] The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and cinnamoyl chloride in the same manner as in Example 204.

[1609] MP: 131-134° C.

[1610] Anal. Calcd. for: C₂₇H₂₆ClN₃O₃:C,68.13;H,5.51;N,8.83.

[1611] Found: C,68.04;H,5.58;N,8.75.

[1612] MS(EI): 475(M⁺).

[1613] IR(KBr): ν=3396,1687,1624,1521,1394,1207,1087 cm⁻¹.

[1614]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.0 Hz), 0.98(3H,t,J=7.1 Hz), 1.62-1.68(2H,m), 2.89-2.91(2H,m), 3.84(2H,q,J=7.0 Hz), 5.60(1H,s), 7.16(1H,dd,J=7.4 and 7.8 Hz), 7.18(1H,d,J=6.3 Hz), 7.26(1H,dd,J=6.3 and 7.4 Hz), 7.39(1H,d,J=7.8 Hz), 7.45(1H,s), 7.46(3H,m), 7.67(1H,d,J=6.1 Hz), 7.69-7.76(2H,m), 7.91(1H,d,J=7.4 Hz), 9.01(1H,s).

Example 229 Ethyl 4-(2-chlorophenyl)-l-cinnamoyl-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1615] Through the column of silica gel column chromatography-used in Example 228 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.

[1616] MS(EI): 475(M⁺).

[1617] IR(KBr): ν=3304,1695,1674,1601,1521,1365,1168,1095 cm⁻¹.

[1618]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.0 Hz), 0.98(3H,t,J=7.3 Hz), 1.65-1.70(2H,m), 2.76-2.87(2H,m), 3.82(2H,q,J=7.0 Hz), 5.62(1H,s), 7.12-7.18(2H,m), 7.24(1H,dd,J=7.3 and 7.3 Hz), 7.42(1H,d,J=7.8 Hz), 7.45-7.46(3H,m), 7.60(1H,d,J=6.1 Hz), 7.62-7.70(2H,m), 7.86(1H,d,J=6.1 Hz), 7.85(1H,s), 10.09(1H,s).

Example 230 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-3-methyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1619] The title compound was obtained as colorless crystals from 2-ethylbenzaldehyde, 3-amino-5-methylpyrazol and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1620] MP: 164-165° C.

[1621] MS(EI): 359(M⁺).

[1622]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.0 Hz), 1.02(3H,t,J=7.3 Hz), 1.61(2H,m), 1.89(3H,s), 2.60-2.85(2H,m), 3.80(2H,q,J=7.0 Hz), 5.44(1H,s), 7.00-7.30(4H,m), 9.39(1H,s), 11.66(1H,s).

Example 231 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-2-methyl-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1623] A solution of ethyl 3-ketohexanoate (7.5 g), 2-chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2-(2-chlorophenyl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture, 2.8 g), 3-amino-1-methylpyrazole (0.25 g) and p-toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals.

[1624] MP: 150-151° C.

[1625] MS(EI): 359(M⁺).

[1626]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83(3H,t,J=7.0 Hz), 0.96(3H,t,J=6.5 Hz), 1.65(2H,m), 2.67-2.85(2H,m), 3.58(3H,s), 3.77(2H,q,J=7.0 Hz), 5.55(1H,s), 7.07-7.11(2H,m), 7.19(1H,dd,J=7.4 and 7.8 Hz), 7.24(1H,d,J=8.3 Hz), 9.45(1H,s).

Example 232 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-1-methyl-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1627] The title compound was obtained as a colorless amorphous solid from ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture), 3-amino-2-methylpyrazole and p-toluenesulfonic acid.

[1628] MS(EI): 359(M⁺).

[1629]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.0 Hz), 1.00(3H,t,J=7.1 Hz), 1.67-1.69(2H,m), 2.70-2.88(2H,m), 3.65(3H,s), 3.80(2H,q,J=7.0 Hz), 5.55(1H,s), 6.96(1H,s), 7.08-7.12(2H,m), 7.20(1H,dd,J=6.8 and 7.8 Hz), 7.35(1H,d,J=7.8 Hz), 9.31(1H,s).

Example 233 Ethyl 4,7-dihydro-1-methyl-4-(naphthalen-1-yl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1630] A solution of ethyl 3-ketohexanoate (6.6 g), 1-naphthaldehyde (7.34 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 mL) was heated under reflux for 3 hours and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(naphthalen-1-yl)methylene-3-oxohexanoate ((E)/(Z) =1:1 mixture) as a yellow oil. The title compound was obtained as a colorless amorphous solid from ethyl 2-(naphthalen-1-yl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture), 3-amino-2-methylpyrazole and p-toluenesulfonic acid.

[1631] MS(EI): 375(M⁺).

[1632]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.60(3H,t,J=6.9 Hz), 1.03(3H,t,J=6.9 Hz), 1.74(2H,m), 2.78-2.85(2H,m), 3.65(3H,s), 3.68(2H,q,J=6.9 Hz), 5.94(1H,s), 6.76(1H,s), 7.20(1H,d,J=7.3 Hz), 7.37(1H,dd,J=7.4 and 7.8 Hz), 7.50(1H,dd,J=6.9 and 7.8 Hz), 7.58(1H,m), 7.67(1H,d,J=8.3 Hz), 7.88(1H,d,J=8.3 Hz), 8.42(1H,d,J=8.8 Hz), 9.26(1H,s).

Example 234 Ethyl 4-(3-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1633] The title compound was obtained as colorless crystals from 3-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1634] MP: 140-143° C.

[1635] Anal. Calcd. for: C₁₈H₂₀ClN₃O₂ 2/5 H₂O:C,61.24;H,5.94;N,11.90.

[1636] Found: C,61.50;H,5.94;N,11.99.

[1637] MS(EI): 345(M⁺).

[1638] IR(KBr): ν=3263,1736,1666,1591,1514,1275,1222,1207,1087 cm⁻¹.

[1639]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.0 Hz), 1.04(3H,t,J=7.1 Hz), 1.58-1.63(2H,m), 2.63-2.81(2H,m), 3.86(2H,q,J=7.0 Hz), 5.11(1H,s), 7.08(1H,d,J=7.8 Hz), 7.12(2H,m), 7.21(1H,d,J=8.3 Hz), 7.26(1H,s), 9.84(1H,s), 11.99(1H,s).

Example 235 Ethyl 4-(4-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1640] The title compound was obtained as colorless crystals from 4-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1641] MP: 159-161° C.

[1642] Anal. Calcd. for: C₁₈H₂₀ClN₃O₂ 1/5 H₂O:C,61.87;H,5.88;N,12.03.

[1643] Found: C,61.92;H,6.23;N,11.95.

[1644] MS(EI): 345(M⁺).

[1645] IR(KBr): ν=3263,1730,1662,1593,1516,1207,1091 cm⁻¹.

[1646]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.0 Hz), 0.95(3H,t,J=7.3 Hz), 1.60(2H,m), 2.64-2.80(2H,m), 3.84(2H,q,J=7.0 Hz), 5.10(1H,s), 7.13(2H,d,J=7.3 Hz), 7.22(1H,s), 7.25(2H,d,J=7.3 Hz), 9.45(1H,s), 11.96(1H,s).

Example 236 Ethyl 4,7-dihydro-4-(4-methyl-1H-imidazol-5-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1647] The title compound was obtained as colorless crystals from 4-methyl-5-imidazolecarboxaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1648] MP: 219-220° C.

[1649] Anal. Calcd. for: C₁₆H₂₁N₅O₂ 1/2 H₂O:C,59.61;H,6.25;N,21.72.

[1650] Found: C,59.34;H,6.48;N,22.06.

[1651] MS(EI): 315(M⁺).

[1652] IR(KBr): ν=3113,2980,1687,1620,1568,1244,1159 cm⁻¹.

[1653]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.08(3H,t,J=7.0 Hz), 1.58-1.59(2H,m), 2.21(3H,s), 2.58-2.79(2H,m), 3.97(2H,q,J=7.3 Hz), 5.50(1H,s), 6.14(1H,s), 7.14(1H,s), 7.19(1H,s), 9.78(1H,s), 11.53(1H,s).

Example 237 Ethyl 4,7-dihydro-4-(1-methyl-1H-imidazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1654] The title compound was obtained as colorless crystals from 1-methyl-2-imidazolecarboxaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1655] MP: 209° C.

[1656] Anal. Calcd. for: C₁₆H₂₁N₅O₂ 3/5 H₂O:C,59.28;H,6.28;N,21.60.

[1657] Found: C,59.00;H,6.52;N,21.55.

[1658] MS(EI): 315(M⁺).

[1659] IR(KBr): ν=3254,3184,3080,1685,1593,1518,1278,1207,1078 cm⁻¹.

[1660]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=6.8 Hz), 0.93(3H,t,J=7.3 Hz), 1.55-1.61(2H,m), 2.57-2.80(2H,m), 3.44(3H,s), 3.87(2H,q,J=6.8 Hz), 5.29(1H,s), 6.56(1H,s), 6.84(1H,s), 7.27(1H,s), 9.38(1H,s), 11.97(1H,s).

Example 238 Ethyl 4,7-dihydro-4-(1H-imidazol-5-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1661] The title compound was obtained as colorless crystals from 3-imidazolecarboxyaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.

[1662] MP: 200° C.

[1663] Anal. Calcd. for: C₁₅H₁₇N₅O₂ 1/2 H₂O:C,58.43;H,5.88;N,22.71.

[1664] Found: C,58.53;H,6.25;N,22.93.

[1665] MS(EI): 301(M⁺).

[1666] IR(KBr): ν=3217,1655,1585,1506,1226,1205,1084 cm⁻¹.

[1667]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.01(3H,t,J=7.3 Hz), 1.57-1.59(2H,m), 2.59-2.74(2H,m), 3.90(2H,q,J=7.3 Hz), 5.12(1H,s), 6.35(1H,s), 7.35(1H,s), 7.38(1H,s), 9.21(1H,s), 11.91(1H,s).

Example 239 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-6-butyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1668] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.

[1669] MP: 213° C.

[1670] Anal. Calcd. for: C₁₉H₂₁N₅O₃:C,62.11;H,5.76;N,19.06.

[1671] Found: C,62.08;H,5.75;N,18.95.

[1672] MS(EI): 367(M⁺).

[1673]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.77(3H,t,J=7.3 Hz), 0.92(3H,t,J=7.3 Hz), 1.32-1.40(2H,m), 1.60-1.64(2H,m), 2.76-2.86(2H,m), 3.76-3.82(2H,m), 5.68(1H,s), 7.11(1H,d,J=6.6 Hz), 7.22(1H,s), 7.51(1H,dd,J=9.0 Hz and 6.6 Hz), 7.77(1H,d,J=9.0 Hz), 9.65(1H,s), 12.00(1H,s).

Example 240 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1674] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.

[1675] MP: 196° C.

[1676] Anal. Calcd. for: C₁₇H₁₇N₅O₃:C,60.17;H,5.05;N,20.64.

[1677] Found: C,60.09;H,5.15;N,20.41.

[1678] MS(EI): 339(M⁺).

[1679]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.75 (3H,t,J=7.3 Hz), 1.21 (3H,t,J=7.3 Hz), 2.83(2H,q,J=7.3 Hz), 3.73-3.84(2H,m), 5.68(1H,s), 7.12(1H,d,J=6.6 Hz), 7.22(1H,s), 7.50(1H,dd,J=9.0 Hz and 6.6 Hz), 7.77(1H,d,J=9.0 Hz), 9.68(1H,s), 12.01(1H,s).

Example 241 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1680] The title compound was prepared from methyl thiophene-2-carboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1681] MP: 174° C.

[1682] Anal. Calcd. for: C₁₇H₁₁ClN₄S 1/10 H₂O:C,59.94;H,3.31;N,16.45.

[1683] Found: C,59.82;H,3.48;N,16.93.

[1684] MS(EI): 338(M⁺).

[1685]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.50(1H,s), 7.18(1H,dd,J=7.3 Hz and 7.2 Hz), 7.24-7.35(4H,m), 7.45(1H,d,J=7.8 Hz), 7.60(1H,d,J=3.6 Hz), 7.77(1H,d,J=3.9 Hz), 10.08(1H,s), 12.29(1H,s)

Example 242 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1686] The title compound was prepared from methyl thiophene-2-carboxylate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1687] MP: 215° C.

[1688] Anal. Calcd. for: C₁₈H₁₄N₄OS: C,64.65;H,4.22;N,16.75.

[1689] Found: C,64.66;H,4.32;N,17.02.

[1690] MS(EI): 334(M⁺).

[1691]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.85(3H,s), 5.34(1H,s), 6.93(1H,dd,J=7.3 Hz and 7.2 Hz), 7.01(1H,d,J=7.3 Hz), 7.14-7.25(4H,m), 7.60(1H,d,J=3.6 Hz), 7.77(1H,d,J=5.1 Hz), 9.91(1H,s), 12.17(1H,s).

Example 243 5-Cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1692] The title compound was prepared from methyl thiophene-2-carboxylate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1693] MP: 222° C.

[1694] Anal. Calcd. for: C₁₈H₁₄N₄S₂ 2/5 H₂O:C,60.44;H,4.17;N,15.66.

[1695] Found: C,60.58;H,4.44;N,15.35.

[1696] MS(EI): 350(M⁺).

[1697]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.49(3H,s), 5.48(1H,s), 7.17-7.28(5H,m), 7.33(1H,d,J=7.3 Hz), 7.60(1H,d,J=3.7 Hz), 7.77(1H,d,J=3.9 Hz), 10.01(1H,s), 12.22(1H,s).

Example 244 5-Cyano-4,7-dihydro-4-(2-nitrophenyl)-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1698] The title compound was prepared from methyl thiophene-2-carboxylate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1699] MP: 165° C.

[1700] Anal. Calcd. for: C₁₇H₁₁N₅O₂S: C,58.44;H,3.17;N,20.05.

[1701] Found: C,58.15;H,3.42;N,20.38.

[1702] MS(EI): 349(M⁺).

[1703]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 7.18(1H,dd,J=7.3 Hz and 7.2 Hz), 7.34(1H,s), 7.48-7.55(2H,m), 7.60(1H,d,J=3.7 Hz), 7.72-7.79(2H,m), 7.92(1H,d,J=8.1 Hz), 10.16(1H,s), 12.35(1H,s).

Example 245 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1704] The title compound was prepared from methyl thiophene-2-carboxylate, 2,1,3-benzothiadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1705] MP: 254° C.

[1706] Anal. Calcd. for: C₁₇H₁₀N₆S₂:C,56.34;H,2.78;N,23.19.

[1707] Found: C,56.01;H,2.91;N,23.19.

[1708] MS(EI): 362(M⁺).

[1709]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.84(1H,s), 7.19(1H,dd,J=4.4 Hz and 4.3 Hz), 7.28(1H,s), 7.55(1H,d,J=6.8 Hz), 7.65(1H,d,J=3.7 Hz), 7.72-7.79(2H,m), 7.99(1H,d,J=8.8 Hz), 10.14(1H,s), 12.21(1H,s).

Example 246 5-Cyano-4,7-dihydro-4-(naphthalen-1-yl)-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1710] The title compound was prepared from methyl thiophene-2-carboxylate, naphthalene-1-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1711] MP: 214° C.

[1712] Anal. Calcd. for: C₂₁H₁₄N₄S: C,71.16;H,3.98;N,15.81.

[1713] Found: C,70.75;H,3.96;N,15.85.

[1714] MS(EI): 354(M⁺).

[1715]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.87(1H,s), 7.13(1H,s), 7.18(1H,dd,J=4.6 Hz and 3.9 Hz), 7.45-7.54(4H,m), 7.62(1H,d,J=3.9 Hz), 7.78(1H,d,J=4.9 Hz), 7.83(1H,d,J=8.1 Hz), 7.95(1H,d,J=9.3 Hz), 8.31(1H,d,J=7.3 Hz), 10.09(1H,s), 12.17(1H,s).

Example 247 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1716] The title compound was prepared from methyl thiophene-2-carboxylate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1717] MP: 232° C.

[1718] Anal. Calcd. for: C₁₇H₁₀Cl₂N₄S 1/10 H₂O:C,54.44;H,2.74;N,14.94.

[1719] Found: C,54.08;H,2.90;N,15.29.

[1720] MS(EI): 373(M⁺).

[1721]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.58(1H,s), 7.18(1H,dd,J=7.3 Hz and 7.2 Hz), 7.32-7.41(3H,m), 7.54(1H,dd,J=7.3 Hz and 1.5 Hz), 7.60(1H,d,J=3.7 Hz), 7.78(1H,d,J=4.9 Hz), 10.14(1H,s), 12.32(1H,s).

Example 248 5-Cyano-4,7-dihydro-4-(2-methylphenyl)-6-phenyl-2H-pyrazolo[3,4-b]pyridine

[1722] The title compound was prepared from methyl benzoate, 2-methylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1723] MP: 246° C.

[1724] Anal. Calcd. for: C₂₀H₁₆N₄ 1.0 H₂O:C,72.71;H,5.49;N,16.96.

[1725] Found: C,72.50;H,5.26;N,17.20.

[1726] MS(EI): 312(M⁺).

[1727]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.38(3H,s), 5.29(1H,s), 7.11-7.23(5H,m), 7.47-7.49(3H,m), 7.55-7.58(2H,m), 9.94(1H,s), 12.17(1H,s).

Example 249 5-Cyano-4,7-dihydro-4-(2-methylphenyl)-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1728] The title compound was prepared from methyl thiophene-2-carboxylate, 2-methylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1729] MP: 276° C.

[1730] Anal. Calcd. for: C₁₈H₁₄N₄S: C,67.90;H,4.43;N,17.60.

[1731] Found: C, 67.93;H,4.54;N,17.64.

[1732] MS(EI): 318(M⁺).

[1733]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.36(3H,s), 5.28(1H,s), 7.11-7.18(5H,m), 7.24(1H,s), 7.55(1H,dd,J=3.7 Hz and 1.0 Hz), 7.74(1H,dd,J=5.9 Hz and 1.0 Hz), 9.95(1H,s), 12.22(1H,s).

Example 250 4-(2-Chlorophenyl)-5-cyano-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1734] The title compound was prepared from methyl dimethoxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1735]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.39(6H,s), 5.18(1H,s), 5.43(1H,s), 7.23-7.27(3H,m), 7.32-7.35(1H,m), 7.44(1H,d,J=7.8 Hz), 9.65(1H,s), 12.21(1H,s).

Example 251 4-(2-Chlorophenyl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1736] 4-(2-Chlorophenyl)-5-cyano-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (4.4 g) was added to trifluoroacetic acid (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and crystallized from ethyl acetate (50 ml) to give the title compound (1.9 g) as yellow crystals.

[1737]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.63(1H,s), 7.27-7.46(5H,m), 7.48(1H,d,J=7.1 Hz), 9.73(1H,s), 10.17(1H,s), 12.34(1H,s).

Example 252 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-hydroxymethyl-2H-pyrazolo[3,4-b]pyridine

[1738] To a suspension of 4-(2-chlorophenyl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (400 mg) in methanol (10 ml) was added sodium borohydride (53 mg) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. 10% Hydrochloric acid was added to the reaction mixture, and a saturated sodium hydrogencarbonate solution was added. The precipitated crystals were collected by filtration and washed with ethanol to give the title compound (295 mg) as yellow crystals.

[1739] MP: 205-210° C. (decomposition)

[1740] Anal. Calcd. for: C₁₄H₁₁ClN₄O 1/4 H₂O:C,57.74;H,3.98;N,19.24.

[1741] Found: C,57.38;H,3.93;N,18.94.

[1742] MS(EI): 286(M⁺).

[1743]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 4.29(2H,d,J=5.6 Hz), 5.38(1H,s), 5.49(1H,t,J=5.6 Hz), 7.22-7.34(4H,m), 7.43(1H,d,J=8.0 Hz), 9.60(1H,s), 12.17(1H,s).

Example 253 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(trans-2-ethoxycarbonylethenyl)-2H-pyrazolo[3,4-b]pyridine

[1744] To a suspension of sodium hydride (94 mg) in dimethoxyethane (10 ml) was added ethyl diethylphosphonoacetate (528 mg) and the mixture was stirred at room temperature for 15 minutes. Under ice-cooling, 4-(2-chlorophenyl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (670 mg) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (560 mg) as yellow crystals.

[1745] MP: 240-243° C. (decomposition).

[1746] Anal. Calcd. for: C₁₈H₁₅ClN₄O₂ 1/2 H₂O:C,59.43;H,4.43;N,15.40.

[1747] Found: C,59.53;H,4.26;N,15.31.

[1748] MS(EI): 354(M⁺).

[1749]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.25(3H,d,J=7.1 Hz), 4.21(2H,q,J=7.1 Hz), 5.52(1H,s), 6.93(1H,d,J=15.9 Hz), 7.27-7.46(6H,m), 10.09(1H,s), 12.31(1H,s).

Example 254 4-(2-Chlorophenyl)-5-cyano-6-(2-ethoxycarbonylethyl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1750] A suspension of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(trans-2-ethoxycarbonylethenyl)-2H-pyrazolo[3,4-b]pyridine (260 mg) and 5% palladium on carbon (110 mg) in ethanol was subjected to catalytic hydrogenation at room temperature for 5 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give a yellow solid. The yellow solid was crystallized from ethyl acetate-diisopropyl ether to give the title compound (160 mg) as pale-yellow crystals.

[1751] MP: 172-174° C.

[1752] MS(EI): 356(M⁺).

[1753]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.18(3H,t,J=7.3 Hz), 2.60-2.80(4H,m), 4.08(2H,q,J=7.3 Hz), 5.35(1H,s), 7.20-7.31(4H,m), 7.42(1H,d,J=8.0 Hz), 9.84(1H,s), 12.16(1H,s).

Example 255 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1754] The title compound was prepared from methyl dimethoxyacetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1755]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.35(3H,s), 3.38(3H,s), 5.16(1H,s), 5.47(1H,s), 7.26(1H,s), 7.42(1H,d,J=6.6 Hz), 7.60(1H,dd,J=6.6,8.5 Hz), 7.94(1H,d,J=8.5 Hz), 9.77(1H,s), 12.19(1H,s).

Example 256 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1756] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 251.

[1757]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.71(1H,s), 7.33(1H,s), 7.56(1H,d,J=6.6 Hz), 7.62(1H,dd,J=6.6,8.8 Hz), 7.98(1H,d,J=8.8 Hz), 9.73(1H,s), 10.32(1H,s), 12.32(1H,s).

Example 257 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-hydroxymethyl-2H-pyrazolo[3,4-b]pyridine

[1758] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 252.

[1759] MP: 215-220° C. (decomposition).

[1760] Anal. Calcd. for: C₁₄H₁₀N₆O₂ 1/2 H₂O:C,55.44;H,3.66;N,27.71.

[1761] Found: C,55.32;H,3.68;N,27.31.

[1762] MS(EI): 294(M⁺).

[1763]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 4.30(2H,s), 5.45(1H,s), 5.52(1H,brs), 7.27(1H,s), 7.42(1H,d,J=6.6 Hz), 7.59(1H,dd,J=6.6,9.0 Hz), 7.93(1H,d,J=9.0 Hz), 9.71(1H,s), 12.16(1H,s)

Example 258 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(trans-2-ethoxycarbonylethenyl)-2H-pyrazolo[3,4-b]pyridine

[1764] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 253.

[1765]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.24(3H,d,J=7.1 Hz), 4.21(2H,q,J=7.1 Hz), 5.59(1H,s), 6.96(1H,d,J=16.1 Hz), 7.32(1H,s), 7.39(1H,d,J=16.1 Hz), 7.50(1H,m), 7.59(1H,m), 7.96(1H,d,J=8.3 Hz), 10.21(1H,s), 12.29(1H,s).

Example 259 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-(2-ethoxycarbonylethyl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1766] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(trans-2-ethoxycarbonylethenyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 254.

[1767] MS(EI): 364(M⁺).

[1768]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.18(3H,t,J=7.1 Hz), 2.66-2.80(4H,m), 4.08(2H,q,J=7.1 Hz), 5.40(1H,s), 7.26(1H,s), 7.42(1H,d,J=6.6 Hz), 7.58(1H,dd,J=6.6,9.0 Hz), 7.92(1H,d,J=9.0 Hz), 9.96(1H,s), 12.16(1H,s).

Example 260 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[1769] The title compound was prepared from methyl isobutyrate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1770] MP: >250° C.

[1771] Anal. Calcd. for: C₁₇H₁₄BrN₅:C,55.45;H,3.83;N,19.02.

[1772] Found: C,55.30;H,3.91;N,18.98.

[1773] MS(EI): 368(M⁺).

[1774]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.23(3H,d,J=6.8 Hz), 1.27(3H,d,J=6.8 Hz), 3.03(1H,m), 5.45(1H,s), 7.33(1H,s), 7.55-7.82(2H,m), 7.83(1H,dd,J=2.0, 7.1 Hz), 9.76(1H,s), 12.25(1H,s).

Example 261 4-(2-Bromophenyl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine acetonitrile

[1775] The title compound was prepared from methyl isobutyrate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1776] MP: >250° C.

[1777] Anal. Calcd. for: C₁₆H₁₅BrN₄C₂H₃N:C,56.26;H,4.72;N,18.22.

[1778] Found: C,56.05;H,4.56;N,17.09.

[1779] MS(EI): 343(M⁺).

[1780]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.24(3H,d,J=7.1 Hz), 1.27(3H,d,J=7.1 Hz), 2.06(3H,s), 3.06(1H,m), 5.23(1H,s), 7.13-7.18(1H,m), 7.22(1H,d,J=7.6 Hz), 7.27(1H,s), 7.36(1H,dd,J=1.2,7.6 Hz), 7.59(1H,dd,J=1.2,8.0 Hz), 9.64(1H,s), 12.17(1H,s).

Example 262 5-Cyano-4,7-dihydro-6-isopropyl-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[1781] The title compound was prepared from methyl isobutyrate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1782] MP: 224° C.

[1783] MS(EI): 309(M⁺).

[1784]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.23(3H,d,J=7.1 Hz), 1.28(3H,d,J=7.1 Hz), 3.03(1H,m), 5.36(1H,s), 7.27(1H,s), 7.43-7.49(2H,m), 7.70(1H,dd,J=1.2,8.8 Hz), 7.89(1H,dd,J=1.2,8.3 Hz), 9.71(1H,s), 12.23(1H,s).

Example 263 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[1785] The title compound was prepared from methyl isobutyrate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1786] MP: >250° C.

[1787] Anal. Calcd. for: C₁₆H₁₄C₁₂N₄:C,57.67;H,4.23;N,16.89.

[1788] Found: C,57.74;H,4.27;N,16.89.

[1789] MS(EI): 333(M⁺).

[1790]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.23(3H,d,J=7.1 Hz), 1.27(3H,d,J=7.1 Hz), 3.04(1H,m), 5.42(1H,s), 7.23(1H,d,J=7.6 Hz), 7.31(1H,s), 7.35(1H,dd,J=7.6,7.8 Hz), 7.51(1H,dd,J=1.5,7.8 Hz), 9.70(1H,s), 12.21(1H,s).

Example 264 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[1791] The title compound was prepared from methyl isobutyrate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1792] MP: 222-223° C. (decomposition)

[1793] Anal. Calcd. for: C₁₆H₁₄N₆O:C,62.71;H,4.61;N,27.44.

[1794] Found: C,62.71;H,4.65;N,27.45.

[1795] MS(EI): 306(M⁺).

[1796]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.24(3H,d,J=7.1 Hz), 1.25(3H,d,J=7.1 Hz), 3.03(1H,m), 5.39(1H,s), 7.26(1H,s), 7.40(1H,d,J=6.6 Hz), 7.58(1H,dd,J=6.6,8.8 Hz), 7.92(1H,d,J=8.8 Hz), 9.74(1H,s), 12.15(1H,s).

Example 265 5-Cyano-4,7-dihydro-6-isopropyl-4-(2-methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine

[1797] The title compound was prepared from methyl isobutyrate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1798] MP: >250° C.

[1799] Anal. Calcd. for: C₁₇H₁₈N₄O:C,69.37;H,6.16;N,19.03.

[1800] Found: C,69.13;H,6.21;N,19.54.

[1801] MS(EI): 294(M⁺).

[1802]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.23(3H,d,J=7.1 Hz), 1.28(3H,d,J=7.1 Hz), 3.09(1H,m), 3.83(3H,s), 5.19(1H,s), 6.90(1H,dd,J=7.4,7.6 Hz), 6.99(1H,d,J=7.6 Hz), 7.05(1H,dd,J=1.7,7.4 Hz), 7.15-7.19(2H,m), 9.47(1H,s), 12.04(1H,s)

Example 266 4-(2-Chlorophenyl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1803] The title compound was prepared from methyl cyclopropanecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1804] MP: >250° C.

[1805] Anal. Calcd. for: C₁₆H₁₃ClN₄:C,64.76;H,4.42;N,18.88.

[1806] Found: C,64.71;H,4.50;N,19.05.

[1807] MS(EI): 296(M⁺).

[1808]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89-0.93(2H,m), 1.00-1.15(2H,m), 2.01(1H,m), 5.35(1H,s), 7.22-7.26(3H,m), 7.31-7.34(1H,m), 7.42(1H,d,J=7.8 Hz), 9.14(1H,s), 12.16(1H,s).

Example 267 4-(2-Bromophenyl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1809] The title compound was prepared from methyl cyclopropanecarboxylate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1810] MP: >250° C.

[1811] Anal. Calcd. for: C₁₆H₁₃BrN₄:C,56.32;H,3.84;N,16.42.

[1812] Found: C,56.18;H,3.90;N,16.48.

[1813] MS(EI): 341(M⁺).

[1814]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-0.93(2H,m), 1.00-1.15(2H,m), 2.01(1H,m), 5.34(1H,s), 7.13-7.22(2H,m), 7.27(1H,s), 7.34-7.38(1H,m), 7.59(1H,d,J=6.8 Hz), 9.15(1H,s), 12.16(1H,s).

Example 268 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 1/4 acetonitrile

[1815] The title compound was prepared from methyl cyclopropanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1816] MP: >250° C.

[1817] Anal. Calcd. for: C₁₇H₁₂BrN₅H₂O 1/4 CH₃CN:C,53.28;H,3.77;N,18.64.

[1818] Found.: C,53.28;H,3.72;N,18.81.

[1819] MS(EI): 366(M⁺).

[1820]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-0.93(2H,m), 1.03-1.08(2H,m), 1.96-2.00(1H,m), 5.45(1H,s), 7.32(1H,s), 7.54-7.60(2H,m), 7.83(1H,dd,J=1.7,7.1 Hz), 9.27(1H,s), 12.25(1H,s).

Example 269 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1821] The title compound was prepared from methyl cyclopropanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1822] MP: 200-201° C. (decomposition).

[1823] Anal. Calcd. for: C₁₆H₁₂N₆O H₂O:C,59.62;H,4.38;N,26.07.

[1824] Found: C,59.93;H,4.05;N,26.19.

[1825] MS(EI): 304(M⁺).

[1826]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88-0.93(2H,m), 1.01-1.12(2H,m), 1.99(1H,m), 5.39(1H,s), 7.25(1H,s), 7.40(1H,d,J=6.6 Hz), 7.59(1H,dd,J=6.6,9.0 Hz), 7.92(1H,d,J=9.0 Hz), 9.26(1H,s), 12.15(1H,s).

Example 270 4-(2-Methoxyphenyl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 1/4 acetonitrile

[1827] The title compound was prepared from methyl cyclopropanecarboxylate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1828] MP: 241-243° C.

[1829] Anal. Calcd. for: C₁₇H₁₆N₄O 1/4 CH₃CN:C,69.46;H,5.58;N,19.67.

[1830] Found: C,69.35;H,5.56;N,19.64.

[1831] MS(EI): 292(M⁺).

[1832]¹ H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-0.92(2H,m), 0.99-1.10(2H,m), 2.01-2.06(1H,m), 3.84(3H,s), 5.21(1H,s), 6.90(1H,dd,J=7.3,7.6 Hz), 6.98-7.05(2H,m), 7.15-7.19(2H,m), 8.97(1H,s), 12.04(1H,s)

Example 271 5-Cyano-6-cyclopropyl-4-(2,3-dichlorophenyl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 1/4 acetonitrile

[1833] The title compound was prepared from methyl cyclopropanecarboxylate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1834] MP: >250° C.

[1835] Anal. Calcd. for: C₁₆H₁₂C₁₂N₄ 1/4 CH₃CN:C,58.04;H,3.76;N,17.43.

[1836] Found: C,57.87;H,3.79;N,17.44.

[1837] MS(EI): 331(M⁺).

[1838]¹H-NMR (400 MHz,DMSO-d₆)6(ppm): 0.90-0.93(2H,m), 1.03-1.08(2H,m), 1.98-2.03(1H,m), 5.43(1H,s), 7.22(1H,d,J=7.8 Hz), 7.31(1H,s), 7.35(1H,t,J=7.8 Hz), 7.51(1H,dd,J=1.5,7.8 Hz), 9.21(1H,s), 12.20(1H,s).

Example 272 5-Cyano-6-cyclopropyl-4,7-dihydro-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[1839] The title compound was prepared from methyl cyclopropanecarboxylate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[1840] MP: 236-238° C. (decomposition)

[1841] Anal. Calcd. for: C₁₆H₁₃N₅O₂:C,62.53;H,4.26;N,22.79.

[1842] Found: C,62.54;H,4.29;N,22.85.

[1843] MS(EI): 307(M⁺).

[1844]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-0.93(2H,m), 1.01-1.09(2H,m), 1.99(1H,m), 5.37(¹H,s), 7.27(1H,s), 7.42-7.49(2H,m), 7.70(1H,dd,J=7.5,7.6 Hz), 7.90(1H,d,J=8.1 Hz), 9.23(1H,s), 12.22(1H,s).

Example 273 Ethyl 4-(2-chlorophenyl)-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1845] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4,4-dimethoxy-3-oxobutanoate in the same manner as in Example 1.

[1846]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.87(3H,t,J=7.1 Hz), 3.35(3H,s), 3.46(3H,s), 3.82(2H,m), 5.64(1H,s), 6.11(1H,s), 7.10-7.14(2H,m), 7.20-7.24(1H,m), 7.27(1H,s), 7.36(1H,d,J=8.3 Hz), 8.94(1H,s), 12.05(1H,s).

Example 274 Ethyl 4-(2-chlorophenyl)-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1847] To a solution of ethyl 4-(2-chlorophenyl)-6-dimethoxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (463 mg) in tetrahydrofuran (5 ml) was added 1 N hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (290 mg) as a yellow solid.

[1848]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 3.91(2H,m), 5.70(1H,s), 7.14-7.24(3H,m), 7.31(1H,s), 7.40(1H,d,J=7.8 Hz), 9.64(1H,s), 10.23(1H,s), 12.19(1H,s).

Example 275 Ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1849] 2-Chlorobenzaldehyde (1.41 g), 3-aminopyrazole (0.83 g) and ethyl isobutyrylacetate (1.58 g) were stirred in acetic acid (10 ml) at 80° C. for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The insoluble material was filtered off, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)). The purified product was crystallized from hexane-ethyl acetate to give the title compound (115 mg) as white crystals.

[1850] MP: 211-213° C.

[1851]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.1 Hz), 1.16(3H,m), 1.28(3H,d,J=7.1 Hz), 3.76(2H,m), 4.35(1H,m), 5.59(1H,s), 7.07-7.13(2H,m), 7.18-7.22(1H,m), 7.24(1H,s), 7.35(1H,dd,J=1.2,8.1 Hz), 9.14(1H,s), 11.97(1H,s).

Example 276 Ethyl 4-(2-bromophenyl)-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1852] The title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.

[1853] MP: 214-215° C.

[1854]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=6.8 Hz), 1.16(3H,m), 1.28(3H,d,J=6.8 Hz), 3.76(2H,m), 4.35(1H,m), 5.56(1H,s), 7.07-7.13(2H,m), 7.02(1H,dd,J=7.3,7.8 Hz), 7.11(1H,d,J=6.4 Hz), 7.24(1H,dd,J=7.4,7.8 Hz), 7.28(1H,s), 7.52(1H,d,J=7.8 Hz), 9.15(1H,s), 11.98(1H,s).

Example 277 Ethyl 4-(2-chlorophenyl)-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1855] To a solution of 2-oxazolydone (20.8 g) in tetrahydrofuran (750 ml) was added n-butyllithium (1.56 M hexane solution, 153 ml) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of cyclopropanecarbonyl chloride (25 g) in tetrahydrofuran (50 ml) at −78° C. over 30 minutes. The mixture was stirred for 14 hours while gradually raising the temperature to room temperature. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give white crystals (26 g). A mixture of the obtained white crystals (10 g), ethyl bromoacetate (21.5 ml) and zinc powder (25.3 g) in tetrahydrofuran (300 ml) was ultrasonicated for 2 hours and heated under reflux for 2 hours. To the reaction mixture was added 10% hydrochloric acid and the insoluble material was filtered off through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give ethyl 3-cyclopropyl-3-oxopropionate (5.7 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-cyclopropyl-3-oxopropionate in the same manner as in Example 275.

[1856] MP: 190-192° C.

[1857]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83-0.93(4H,m), 1.10(1H,m), 3.14(¹H,m), 3.80(2H,m), 5.60(21H,s), 7.08-7.12(2H,m), 7.18-7.22(1H,m), 7.25(1H,s), 7.34(1H,d,J=8.3 Hz), 8.62(1H,s), 11.99(1H,s).

Example 278 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1858] The title compound was prepared from methyl thiophene-2-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1859] MP: >280° C.

[1860] Anal. Calcd. for: C₁₈H₁₀BrN₅S:C,52.95;H,2.47;N,17.15.

[1861] Found: C,52.72;H,2.69;N,17.21.

[1862] MS(EI): 408(M⁺).

[1863]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.62(1H,s), 7.18(1H,dd,J=5.1 Hz and 3.7 Hz), 7.40(1H,s), 7.59-7.67(3H,m), 7.79(1H,d,J=3.9 Hz), 7.86(1H,dd,J=7.6 Hz and 2.0 Hz), 10.20(1H,s), 12.37(1H,s).

Example 279 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-methyl-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1864] The title compound was prepared from methyl butanoate 2-chlorobenzaldehyde and 3-amino-5-methylpyrazole in the same manner as in Example 94.

[1865] MP: 260° C.

[1866]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.60-1.65(2H,m), 1.71(3H,s), 2.33(2H,q,J=7.3 Hz), 5.27(1H,s), 7.20-7.24(2H,m), 7.31(1H,dd,J=7.3 Hz and 7.2 Hz), 7.39(1H,d,J=7.3 Hz), 9.68(1H,s), 11.83(1H,s)

Example 280 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-phenyl-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1867] The title compound was prepared from methyl butanoate 2-chlorobenzaldehyde and 3-amino-5-phenylpyrazole in the same manner as in Example 94.

[1868] MP: 262° C.

[1869]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 1.61-1.63(2H,m), 2.36(2H,q,J=7.3 Hz), 5.61(1H,s), 7.09-7.34(9H,m), 9.89(1H,s), 12.62(1H,s)

Example 281 1-tert-Butoxycarbonyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-1 H-pyrazolo[3,4-b]pyridine

[1870] The title compound was obtained as a colorless amorphous solid from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and di-tert-butyl dicarbonate in the same manner as in Example 204.

[1871] MP: 98-102° C.

[1872] MS(EI): 398(M⁺).

[1873] IR(KBr): ν=3391,2199,1723,1643,1529,1394,1149 cm⁻¹.

[1874]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.57(3H,s), 1.60-1.67(2H,m), 2.53-2.61(2H,m), 5.38(1H,s), 7.25-7.31(3H,m), 7.35(1H,ddd,J=1.4,7.3 and 7.8 Hz), 7.45(1H,d,J=8.1 Hz), 9.20(1H,s).

Example 282 2-tert-Butoxycarbonyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1875] Through the column of silica gel column chromatography used in Example 281 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.

[1876] MP: 175° C. (decomposition).

[1877] Anal. Calcd. for: C₂₁H₂₃ClN₄O₂:C,63.23;H,5.81;N,14.05.

[1878] Found: C,62.91;H,5.80;N,13.82.

[1879] MS(EI): 398(M⁺).

[1880] IR(KBr): ν=3329,2197,1747,1612,1523,1369,1311,1151,949 cm⁻¹.

[1881]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.4 Hz), 1.65(2H,q,J=7.3 Hz), 2.40-2.44(2H,m), 2.48(9H,s), 5.32(1H,s), 7.27-7.36(3H,m), 7.45(1H,d,J=7.8 Hz), 7.68 (1H,s), 10.32(1H,s).

Example 283 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-1-phenylcarbamoyl-6-propyl-1 H-pyrazolo[3,4-b]pyridine

[1882] The title compound was obtained as a colorless amorphous solid from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and phenyl isocyanate in the same manner as in Example 204.

[1883] MP: 138-140° C.

[1884] Anal. Calcd. for: C₂₃H₂₀ClN₅O 1/4 H₂O:C,654;H,4.89;N,16.58.

[1885] Found: C,65.20;H,5.05;N,16.17.

[1886] MS(EI): 417(M⁺).

[1887] IR(KBr): ν=3387,3294,2202,1712,1537 cm⁻¹.

[1888]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.63(2H,q,J=7.4 Hz), 2.58(2H,m), 5.43(1H,s), 7.13(1H,dd,J=7.4 and 7.5 Hz), 7.24-7.36(6H,m), 7.46(1H,d,J=7.8 Hz), 7.69(2H,d,J=7.8 Hz), 9.46(1H,s), 10.38(1H,s).

Example 284 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-2-phenylcarbamoyl-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1889] Through the column of silica gel column chromatography used in Example 283 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless oil.

[1890] MP: 167-171° C.

[1891] MS(EI): 417(M⁺).

[1892] IR(KBr): ν=3215,2204,1732,1631,1523,1375 cm⁻¹. ¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.97(3H,t,J=7.4 Hz), 1.65(2H,q,J=7.3 Hz), 2.48(2H,m), 5.39(1H,s), 6.95(1H,dd,J=7.3 and 7.3 Hz), 7.11(2H,dd,J=7.3 and 7.6 Hz), 7.24-7.49(4H,m), 7.61(2H,d,J=7.8 Hz), 7.88(1H,s), 8.63(1H,s), 9.77(1H,s), 10.17(1H,s).

Example 285 2-Acetoxyacetyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1893] The title compound was obtained as colorless crystals from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and acetoxyacetyl chloride in the same manner as in Example 204.

[1894] MP: 149-150° C.

[1895] Anal. Calcd. for: C₂₀H₁₉ClN₄O₃:C,60.23;H,4.80;N,14.05.

[1896] Found: C,60.17;H,4.83;N,13.90.

[1897] MS(EI): 398(M⁺).

[1898] IR(KBr): ν=3281,3238,2197,1745,1630,1608,1523,1385,1344,1236, 1172 cm⁻¹.

[1899]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 2.44(2H,q,J=7.3 Hz), 3.33(3H,s), 5.26(2H,s), 5.37(1H,s), 7.29-7.35(3H,m), 7.46(1H,d,J=7.8 Hz), 7.86(1H,s), 10.45(1H,s).

Example 286 Ethyl 1-acetoxyacetyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1900] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and acetoxyacetyl chloride in the same manner as in Example 204.

[1901] MP: 130-131° C.

[1902] Anal. Calcd. for: C₂₂H₂₄ClN₃O₅:C,59.26;H,5.43;N,9.42.

[1903] Found: C,59.17;H,5.39;N,9.31.

[1904] MS(EI): 445(M⁺).

[1905] IR(KBr): ν=3337,1732,1529,1390,1246,1086 cm⁻¹.

[1906]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.0 Hz), 0.97(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 2.76-2.82(2H,m), 3.31(3H,s), 3.85(2H,q,J=7.0 Hz), 5.27(2H,dd,J=3.0 and 9.8 Hz), 5.60(1H,s), 7.10-7.25(3H,m), 7.41(1H,dd,J=1.4 and 8.0 Hz), 7.82(1H,s), 10.1(1H,s).

Example 287 Ethyl 1-benzylcarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate

[1907] The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenylacetyl chloride in the same manner as in Example 204.

[1908] MS(EI): 463(M⁺).

[1909] IR(KBr): ν=3418,1701,1521,1392,1228 cm⁻¹.

[1910]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.0 Hz), 0.93(3H,t,J=7.3 Hz), 1.57-1.62(2H,m), 2.80-2.87(2H,m), 3.82(2H,q,J=7.0 Hz), 4.33(2H,s), 5.57(1H,s), 7.15(1H,dd,J=7.4 and 7.8 Hz), 7.18-7.31(7H,m), 7.39(1H,d,J=7.8 Hz), 7.44(1H,s), 8.94(1H,s).

Example 288 4-(2,1,3-Benzoxadiazol-4-yl)-2-tert-butoxycarbonyl-5-cyano-4,7-dihydro-6-propyl-2 H-pyrazolo[3,4-b]pyridine

[1911] The title compound was obtained as colorless crystals from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-1 H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and tert-butyldicarbonate in the same manner as in Example 204.

[1912] MP: 168-170° C.

[1913] Anal. Calcd. for: C₂₁H₂₂N₆O₃:C,62.06;H,5.46;N,20.68.

[1914] Found: C,61.92;H,5.44;N,20.52.

[1915] MS(EI): 406(M⁺).

[1916]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 1.47(9H,s), 1.65(2H,m), 2.40(2H,m), 5.39(1H,s), 7.49(1H,d,J=6.3 Hz), 7.60(1H,dd,J=6.6 and 9.0 Hz), 7.79(1H,s), 7.96(1H,d,J=6.6 Hz), 10.43(1H,s).

Example 289 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-1-phenylcarbamoyl-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1917] The title compound was obtained as colorless crystals from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and phenyl isocyanate in the same manner as in Example 204.

[1918] MP: 138-140° C.

[1919] Anal. Calcd. for: C₂₃H₁₉N₇O₂:C,64.93;H,4.50; N,23.05.

[1920] Found: C,65.07;H,5.05;N,21.24.

[1921] MS(EI): 425(M⁺).

[1922]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.62(2H,m), 2.58(2H,m), 5.47(1H,s), 7.13(1H,dd,J=6.3 and 6.6 Hz), 7.32-7.39(3H,m), 7.49(1H,d,J=6.5 Hz), 7.61-7.91(3H,m), 7.98(1H,d,J=9.1 Hz), 9.54(1H,s), 10.34(1H,s).

[1923] The compounds of the above-described Examples are as follows.

Example 290 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(4-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1924] To a solution of acetonitrile (15 g) in DMSO (25 mL) was added methyl p-anisate (25 g) and the mixture was stirred with heating at 60° C. for 1 hour. The reaction mixture was allowed to cool and cold water (100 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methoxybenzoylacetonitrile (21 g) as colorless crystals. To a solution of the obtained crystals in toluene was added hydrazine monohydrate (13 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the precipitated crystals were collected by filtration to give 5-amino-3-(4-methoxyphenyl)pyrazole (22 g). Subsequently, the title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 5-amino-3-(4-methoxyphenyl)pyrazole in the same manner as in Example 94.

[1925] MP: 284° C.

[1926] Anal. Calcd. for: C₂₃H₂₁ClN₄O:C,68.23;H,5.23;N,13.84.

[1927] Found: C,68.17;H,5.29;N,13.86.

[1928] MS(EI): 404(M⁺).

[1929]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 1.58-1.63(2H,m), 2.32-2.38(2H,m), 3.70(3H,s), 5.56(1H,s), 6.81(2H,d,J=7.2 Hz), 7.09-7.12(2H,m), 7.17(1H,dd,J=7.3 Hz and 7.2 Hz), 7.24-7.30(3H,m), 9.85(1H,brs), 12.46(1H,brs).

Example 291 4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-bromothiophen-5-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1930] The title compound was prepared from methyl 5-bromothiophene-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1931] MP: 208° C.

[1932] Anal. Calcd. for: C₁₇H₉BrN₆OS:C,48.01;H,2.13;N,19.76.

[1933] Found: C,47.94;H,2.36;N,19.78.

[1934] MS(EI): 425(M⁺).

[1935]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 7.32-7.34(2H,m), 7.42(1H,d,J=3.9 Hz), 7.50(1H,d,J=6.6 Hz), 7.61(1H,dd,J=9.0 Hz), 7.95(1H,d,J=9.0 Hz), 10.32(1H,brs), 12.32(1H,brs).

Example 292 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(3-methylthiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1936] The title compound was prepared from methyl 3-methylthiophene-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1937] MP: 202° C.

[1938] Anal. Calcd. for: C₁₈H₁₂N₆OS:C,59.99;H,3.36;N,23.32.

[1939] Found: C,59.89;H,3.53;N,23.06.

[1940] MS(EI): 360(M⁺).

[1941]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.17(3H,s), 5.54(1H,s), 6.96(1H,d,J=5.1 Hz), 7.32(1H,s), 7.49(1H,d,J=6.6 Hz), 7.60-7.64(2H,m), 7.96(1H,d,J=9.0 Hz), 10.19(1H,brs), 12.25(1H,brs).

Example 293 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methoxymethylindol-3-yl)-2H-pyrazolo[3,4-b]pyridine

[1942] The title compound was prepared from methyl 1-methoxymethylindol-3-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1943] MP: 200° C.

[1944] MS(EI): 423(M⁺).

[1945]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.19(3H,s), 5.55-5.63(3H,m), 7.15(1H,dd,J=7.3 Hz and 7.2 Hz), 7.25(1H,dd,J=7.3 Hz and 7.2 Hz), 7.34(1H,s), 7.54(1H,d,J=7.3 Hz), 7.60-7.66(3H,m), 7.93-7.97(2H,m), 10.12(1H,brs), 12.22(1H,brs).

Example 294 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-3-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine

[1946] The title compound was prepared from methyl thiophene-2-carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.

[1947] MP: 256° C.

[1948] Anal. Calcd. for: C₂₀H₁₇ClN₄S:C,63.07;H,4.50;N,14.71.

[1949] Found: C,62.98;H,4.52;N,14.68.

[1950] MS(EI): 380(M⁺).

[1951]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.3 Hz), 1.56-1.62(2H,m), 2.31-2.36(2H,m), 5.46(1H,s), 7.00-7.24(5H,m), 7.36(1H,d,J=7.3 Hz), 7.50(1H,d,J=4.9 Hz), 9.95(1H,brs), 12.74(1H,brs)

Example 295 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(furan-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1952] The title compound was prepared from methyl furan-2-carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.

[1953] MP: 253° C.

[1954] Anal. Calcd. for: C₂₀H₁₇ClN₄O:C,65.84;H,4.70;N,15.36.

[1955] Found: C,65.81;H,4.84;N,15.49.

[1956] MS(EI): 364 (M⁺).

[1957]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 1.58-1.63(2H,m), 2.32-2.36(2H,m), 5.48(1H,s), 6.31(1H,d,J=3.2 Hz), 6.45(1H,d,J=1.5 Hz), 7.14-7.23(3H,m), 7.36(1H,d,J=7.3 Hz), 7.59(1H,s), 9.93(1H,brs), 12.76(1H,brs).

Example 296 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(2-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1958] The title compound was prepared from methyl 2-methoxybezoate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.

[1959] MP: >270° C.

[1960] Anal. Calcd. for: C₂₃H₂₁ClN₄O:C,68.23;H,5.23;N,13.84.

[1961] Found: C,68.23;H,5.31;N,13.87.

[1962] MS(EI): 404(M⁺).

[1963]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90(3H,t,J=7.3 Hz), 1.60-1.65(2H,m), 2.32-2.36(2H,m), 3.70(3H,s), 5.41(1H,s), 6.76(1H,dd,J=7.3 Hz and 7.2 Hz), 6.90-6.94(2H,m), 6.98-7.04(2H,m), 7.08-7.15(2H,m), 7.22(1H,dd,J=7.3 Hz and 7.2 Hz), 9.83(1H,brs), 12.21(1H,brs).

Example 297 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(3-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1964] The title compound was prepared from methyl 3-methoxybenzoate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.

[1965] MP: 239° C.

[1966] Anal. Calcd. for: C₂₃H₂₁ClN₄O:C,68.23;H,5.23;N,13.84.

[1967] Found: C,68.16;H,5.31;N,13.80.

[1968] MS(EI): 404(M⁺).

[1969]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 1.58-1.63(2H,m), 2.31-2.36(2H,m), 3.68(3H,s), 6.78(1H,d,J=7.3 Hz), 6.87-6.89(2H,m), 7.11-7.20(4H,m), 7.29(1H,d,J=7.3 Hz), 9.92(1H,brs), 12.64(1H,brs).

Example 298 4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-chlorothiophen-5-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[1970] The title compound was prepared from methyl 5-chlorothiophene-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1971] MP: 210° C.

[1972] Anal. Calcd. for: C₁₇H₉ClN₆OS:C,53.62;H,2.38;N,22.07.

[1973] Found: C,53.51;H,2.67;N,22.13.

[1974] MS(EI): 380(M⁺).

[1975]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.54(1H,s), 7.23(1H,d,J=3.9 Hz), 7.33(1H,s), 7.46(1H,d,J=3.9 Hz), 7.50(1H,d,J=6.6 Hz), 7.60(1H,dd,J=9.0 Hz and 6.6 Hz), 7.95(1H,d,J=9.0 Hz), 10.31(1H,brs), 12.30(1H,brs).

Example 299 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-methylthiophen-5-yl)-2H-pyrazolo[3,4-b]pyridine

[1976] The title compound was prepared from methyl 5-methylthiophene-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[1977] MP: 192° C.

[1978] MS(EI): 360(M⁺).

[1979]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.50(3H,s), 5.52(1H,s), 6.87(1H,d,J=3.6 Hz), 7.32(1H,s), 7.40(1H,d,J=3.7 Hz), 7.48(1H,d,J=6.6 Hz), 7.61(1H,dd,J=9.0 Hz and 6.6 Hz), 7.95(1H,d,J=9.0 Hz), 10.12(1H,brs), 12.26(1H,brs).

Example 300 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(naphthalen-1-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1980] The title compound was prepared from methyl naphthalene-1-carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.

[1981] MP: 254° C.

[1982] Anal. Calcd. for: C₂₆H₂₁ClN₄:C,73.49;H,4.98;N,13.19.

[1983] Found: C,73.81;H,5.05;N,13.08.

[1984] MS(EI): 424(M⁺).

[1985]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.64-1.70(2H,m), 2.46-2.49(2H,m), 5.25(1H,s), 6.88-7.02(5H,m), 7.31(1H,dd,J=7.3 Hz and 7.2 Hz), 7.42-7.47(3H,m), 7.83-7.88(2H,m), 9.95(1H,brs), 12.46(1H,brs).

Example 301 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(naphthalen-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1986] The title compound was prepared from methyl naphthalene-2-carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.

[1987] MP: >270° C.

[1988] Anal. Calcd. for: C₂₆H₂₁ClN₄:C,73.49;H,4.98;N,13.19.

[1989] Found: C,73.23;H,5.01;N,13.26.

[1990] MS(EI): 424(M⁺).

[1991]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.61-1.66(2H,m), 2.31-2.41(2H,m), 5.76(1H,s), 7.05(1H,dd,J=7.3 Hz and 7.2 Hz), 7.12-7.16(2H,m), 7.28(1H,d,J=7.3 Hz), 7.45-7.52(2H,m), 7.57(1H,d,J=7.3 Hz), 7.77-7.84(4H,m), 9.94(1H,brs), 12.79(1H,brs)

Example 302 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3,6-dipropyl-2H-pyrazolo[3,4-b]pyridine

[1992] To a solution of acetonitrile (4.8 g) in THF (150 mL) was added n-BuLi (67 mmol) at −78° C. Methyl butyrate (10 g) was added and the mixture was stirred for 1 hour. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyanopentan-2-one (5.5 g) as a colorless oil. To a solution of the obtained colorless oil in toluene was added hydrazine monohydrate (5.0 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol (10:1)) to give 5-amino-3-propylpyrazole (5.0 g). A solution of 2-chloroaldehyde (1.7 g), 5-amino-3-propylpyrazole (1.5 g) and 1-cyanopentan-2-one (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The mixture was cooled to room temperature and the precipitated crystals were collected by filtration to give the title compound (2.1 g) as colorless crystals.

[1993] MP: 237° C.

[1994] Anal. Calcd. for: C₁₉H₂₁ClN₄:C,66.95;H,6.21;N,16.44.

[1995] Found: C,66.98;H,6.26;N,16.41.

[1996] MS(EI): 340(M⁺).

[1997]¹ H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.57(3H,t,J=7.3 Hz), 0.91(3H,t,J=7.3 Hz), 1.02-1.07(2H,m), 1.59-1.65(2H,m), 2.01-2.12(2H,m), 2.30-2.38(2H,m), 5.28(1H,s), 7.20-7.23(2H,m), 7.30(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.70(1H,brs), 11.85(1H,brs).

Example 303 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-hydroxy-6-propyl-2H-pyrazolo[3,4-b]pyridine

[1998] The title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 3-amino-5-hydroxypyrazole in the same manner as in Example 94.

[1999] MS(EI): 314(M⁺).

[2000]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 1.56-1.60(2H,m), 2.26-2.38(2H,m), 5.11(1H,s), 7.14-7.21(3H,m), 7.27(1H,dd,J=7.3 Hz and 7.2 Hz), 7.34(1H,d,J=7.3 Hz), 9.64(1H,brs), 10.45(1H,brs).

Example 304 3-Butyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2001] The title compound was prepared from methyl pentanoate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2002] MP: 212° C.

[2003] Anal. Calcd. for: C₂₀H₂₃ClN₄:C,67.69;H,6.53;N,15.79.

[2004] Found: C,67.58;H,6.46;N,15.75.

[2005] MS(EI): 354(M⁺).

[2006]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.64(3H,t,J=7.3 Hz), 0.89-0.98(6H,m), 1.10-1.14(1H,m), 1.59-1.64(2H,m), 2.05-2.16(2H,m), 2.31-2.35(2H,m), 5.28(1H,s), 7.20-7.24(2H,m), 7.29(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.70(1H,brs), 11.85(1H,brs).

Example 305 4-(2,1,3-Benzoxadiazol-4-yl)-6-(benzothiophen-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2007] The title compound was prepared from methyl benzothiophene-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[2008] MP: 220° C.

[2009] Anal. Calcd. for: C₂₁H₁₂N₆OS:C,63.62;H,3.05;N,21.20.

[2010] Found: C,63.58;H,3.29;N,21.09.

[2011] MS(EI): 396(M⁺).

[2012]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.60(1H,s), 7.36(1H,s), 7.44-7.46(2H,m), 7.54(1H,d,J=6.3 Hz), 7.64(1H,dd,J=9.0 Hz and 6.6 Hz), 7.88(1H,s), 7.94-7.98(2H,m), 8.05(1H,d,J=9.0 Hz), 10.40(1H,brs), 12.31(1H,brs)

Example 306 4-(2-Chlorophenyl)-5-cyano-6-cyclohexyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2013] The title compound was prepared from methyl cyclohexanecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2014] MP: 163° C.

[2015] Anal. Calcd. for: C₁₉H₁₉ClN₄ 1/2 H₂0:C,65.61;H,5.80;N,16.11.

[2016] Found: C,65.40;H,5.77;N,15.86.

[2017] MS(EI): 338(M⁺).

[2018]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.16-1.30(3H,m), 1.66-1.85(7H,m), 2.66-2.72(1H,m), 5.33(1H,s), 7.21-7.25(3H,m), 7.32(1H,dd,J=7.3 Hz and 7.2 Hz), 7.41(1H,d,J=7.3 Hz), 9.60(1H,brs), 12.15(1H,brs).

Example 307 6-t-Butyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2019] The title compound was prepared from methyl pivalate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2020] MP: 198° C.

[2021] Anal. Calcd. for: C₁₇H₁₇ClN₄:C,65.28;H,5.48;N,17.91.

[2022] Found: C,64.98;H,5.47;N,17.78.

[2023] MS(EI): 312(M⁺).

[2024]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41(9H,s), 5.33(1H,s), 7.21-7.33(4H,m), 7.41(1H,d,J=7.3 Hz), 8.88(1H,brs), 12.20(1H,brs).

Example 308 4-(2-Chlorophenyl)-5-cyano-3-cyclopropyl-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2025] The title compound was prepared from methyl cyclopropanecarboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2026] MP: 270° C.

[2027] Anal. Calcd. for: C₁₉H₁₉ClN₄:C,67.35;H,5.65;N,16.54.

[2028] Found: C,67.34;H,5.66;N,16.62.

[2029] MS(EI): 338(M⁺).

[2030] 1H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.22-0.25(1H,m), 0.41-0.44(1H,m), 0.50-0.54(1H,m), 0.62-0.66(1H,m), 0.90(3H,t,J=7.3 Hz), 1.25-1.29(1H,m), 1.58-1.63(2H,m), 2.31-2.36(2H,m), 5.33(1H,s), 7.18-7.23(2H,m), 7.30(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.69(1H,brs), 11.73(1H,brs).

Example 309 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-ethyl-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2031] The title compound was prepared from methyl propionate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2032] MP: 269° C.

[2033] Anal. Calcd. for: C₁₈H₁₉ClN₄:C,66.15;H,5.86;N,17.14.

[2034] Found: C,66.27;H,5.86;N,17.25.

[2035] MS(EI): 326(M⁺).

[2036]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.72(3H,t,J=7.3 Hz), 0.91(3H,t,J=7.3 Hz), 1.59-1.64(2H,m), 2.09-2.11(2H,m), 2.31-2.40(2H,m), 5.29(1H,s), 7.20-7.24(2H,m), 7.30(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.70(1H,brs), 11.86(1H,brs).

Example 310 3-t-Butyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2037] The title compound was prepared from methyl pivalate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2038] MP: >270° C.

[2039] Anal. Calcd. for: C₂₀H₂₃ClN₄:C,67.69;H,6.53;N,15.79.

[2040] Found: C,67.55;H,6.56;N,15.66.

[2041] MS(EI): 354(M⁺).

[2042]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 0.95(9H,s), 1.53-1.59(2H,m), 2.26-2.30(2H,m), 5.39(1H,s), 6.97(1H,d,J=7.3 Hz), 7.20(1H,dd,J=7.3 Hz and 7.2 Hz), 7.27(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.73(1H,brs), 11.87(1H,brs).

Example 311 4-(2-Chlorophenyl)-5-cyano-3-cyclohexyl-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2043] The title compound was prepared from methyl cyclohexanecarboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2044] MP: >270° C.

[2045] Anal. Calcd. for: C₂₂H₂₅ClN₄:C,69.37;H,6.62;N,14.71.

[2046] Found: C,69.17;H,6.62;N,14.91.

[2047] MS(EI): 380(M⁺).

[2048]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89-1.17(9H,m), 1.47-1.64(6H,m), 2.06-2.08(1H,m), 2.31-2.38(2H,m), 5.30(1H,s), 7.19-7.23(2H,m), 7.29(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.71(1H,brs), 11.83(1H,brs).

Example 312 4-(2-Chlorophenyl)-5-cyano-6-cycloheptyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2049] The title compound was prepared from methyl cycloheptanecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2050] MP: 146° C.

[2051] MS(EI): 352(M⁺).

[2052]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.42-1.98(12H,m), 2.78-2.81(1H,m), 5.33(1H,s), 7.21-7.24(3H,m), 7.32(1H,dd,J=7.3 Hz and 7.2 Hz), 7.41(1H,d,J=7.3 Hz), 9.61(1H,brs), 12.18(1H,brs).

Example 313 4-(2-Chlorophenyl)-5-cyano-6-cyclobutyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2053] The title compound was prepared from methyl cyclobutanecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2054] MP: 188° C.

[2055] Anal. Calcd. for: C₁₇H₁₅ClN₄:C,65.70;H,4.86;N,18.03.

[2056] Found: C,65.51;H,5.21;N,18.27.

[2057] MS(EI): 310(M⁺).

[2058]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.72-1.77(1H,m), 1.93-1.97(1H,m), 2.09-2.12(2H,m), 2.38-2.43(2H,m), 2.58-2.61(1H,m), 5.33(1H,s), 7.20-7.32(4H,m), 7.41(1H,d,J=7.3 Hz), 9.72(1H,brs), 12.18(1H,brs).

Example 314 4-(2-Chlorophenyl)-5-cyano-3-cyclopentyl-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2059] The title compound was prepared from methyl cyclopentanecarboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2060] MP: >270° C.

[2061] Anal. Calcd. for: C₁₂H₂₃ClN₄:C,68.75;H,6.32;N,15.27.

[2062] Found: C,68.56;H,6.36;N,15.22.

[2063] MS(EI): 366(M⁺).

[2064] 1H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89(3H,t,J=7.3 Hz), 1.31-1.74(10H,m), 2.30-2.37(2H,m), 2.52-2.54(1H,m), 5.30(1H,s), 7.17-7.22(2H,m), 7.28(1H,dd,J=7.3 Hz and 7.2 Hz), 7.37(1H,d,J=7.3 Hz), 9.71(1H,brs), 11.86(1H,brs).

Example 315 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-3-isopropyl-2H-pyrazolo[3,4-b]pyridine

[2065] The title compound was prepared from methyl 2-methylpropionate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2066] MP: >270° C.

[2067] Anal. Calcd. for: C₁₉H₂₁ClN₄:C,66.95;H,6.21;N,16.44.

[2068] Found: C,66.90;H,6.27;N,16.44.

[2069] MS(EI): 340(M⁺).

[2070]¹ H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.67(3H,d,J=7.2 Hz), 0.90(3H,t,J=7.3 Hz), 0.95(3H,d,J=7.3 Hz), 1.57-1.63(2H,m), 2.30-2.35(2H,m), 5.30(1H,s), 7.19-7.23(2H,m), 7.29(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.71(1H,brs), 11.88(1H,brs).

Example 316 4-(2-Chlorophenyl)-5-cyano-6-cyclopentyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2071] The title compound was prepared from methyl cyclopentanecarboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2072] MP: 225° C.

[2073] Anal. Calcd. for: C₁₈H₁₇ClN₄ 1/5 H₂O:C,65.83;H,5.34;N,17.06.

[2074] Found: C,66.02;H,5.51;N,16.62.

[2075] MS(EI): 324(M⁺).

[2076]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.56-1.60(2H,m), 1.78-1.87(6H,m), 3.06-3.10(1H,m), 5.34(1H,s), 7.22-7.26(3H,m), 7.32(1H,dd,J=7.3 Hz and 7.2 Hz), 7.42(1H,d,J=7.3 Hz), 9.61(1H,brs), 12.16(1H,brs).

Example 317 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-cyclopentyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2077] The title compound was prepared from methyl cyclopentanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2078] MP: 247° C.

[2079] MS(EI): 394(M⁺).

[2080]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.52-1.58(2H,m), 1.75-1.82(6H,m), 3.01-3.06(1H,m), 5.46(1H,s), 7.33(1H,s), 7.54-7.58(2H,m), 7.84(1H,d,J=7.3 Hz), 9.73(1H,brs), 12.25(1H,brs).

Example 318 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-cyclopentyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2081] The title compound was prepared from methyl cyclopentanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2082] MP: 193° C.

[2083] Anal. Calcd. for: C₁₈H₁₆N₆O:C, 65.05;H,4.85;N,25.29.

[2084] Found: C,64.72;H,4.98;N,24.86.

[2085] MS(EI): 332(M⁺).

[2086]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.55-1.58(2H,m), 1.80-1.86(6H,m), 3.06-3.09(1H,m), 5.39(1H,s), 7.26(1H,s), 7.38(1H,d,J=6.6 Hz), 7.60(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.72(1H,brs), 12.15(1H,brs).

Example 319 4-(2-Bromo-3-cyanophenyl)-6-t-butyl-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2087] The title compound was prepared from methyl pivalate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2088] MP: 251° C.

[2089] Anal. Calcd. for: C₁₈H₁₆BrN₅ 1/2 H₂O:C,55.25;H,4.38;N,17.90.

[2090] Found: C,55.55;H,4.30;N,18.14.

[2091] MS(EI): 382(M⁺).

[2092]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41(9H,s), 5.46(1H,s), 7.33(1H,s), 7.54-7.60(2H,m), 7.82(1H,d,J=7.3 Hz), 9.00(1H,brs), 12.29(1H,brs)

Example 320 4-(2,1,3-Benzoxadiazol-4-yl)-6-t-butyl-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2093] The title compound was prepared from methyl pivalate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2094] MP: 204° C.

[2095] Anal. Calcd. for: C₁₇H₁₆N₆O 1/2 H₂O:C,63.03;H,5.10;N,25.94.

[2096] Found: C,63.08;H,5.08;N,26.00.

[2097] MS(EI): 320(M⁺).

[2098]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.40(9H,s), 5.37(1H,s), 7.26(1H,s), 7.38(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.02(1H,brs), 12.20(1H,brs).

Example 321 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-cyclobutyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2099] The title compound was prepared from methyl cyclobutanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2100] MP: 278° C.

[2101] Anal. Calcd. for: C₁₈H₁₄BrN₅:C,56.86;H,3.71;N,18.42.

[2102] Found: C,56.57;H,3.79;N,18.48.

[2103] MS(EI): 380(M⁺).

[2104]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.71(1H,m), 1.88-1.95(1H,m), 5 2.06-2.13(2H,m), 2.38-2.47(2H,m), 3.56-3.60(1H,m), 5.45(1H,s), 7.33(1H,s), 7.57-7.59(2H,m), 7.82(1H,d,J=7.3 Hz), 9.84(1H,brs), 12.27(1H,brs).

Example 322 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-cyclobutyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2105] The title compound was prepared from methyl cyclobutanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2106] MP: 194° C.

[2107] Anal. Calcd. for: C₁₇H₁₄N₆O:C,64.14;H,4.43;N,26.40.

[2108] Found: C,64.08;H,4.51;N,26.26.

[2109] MS(EI): 318(M⁺).

[2110]¹ H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.72-1.76(1 H,m), 1.90-1.97(1H,m), 2.10-2.14(2H,m), 2.39-2.46(2H,m), 3.56-3.60(1H,m), 5.38(1H,s), 7.26(1H,s), 7.37(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.82(1H,brs), 12.17(1H,brs).

Example 323 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-cyclohexyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2111] The title compound was prepared from methyl cyclohexanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2112] MP: 210° C.

[2113] Anal. Calcd. for: C₁₉H₁₈N₆O:C,65.88;H,5.24;N,24.26.

[2114] Found: C,65.88;H,5.25;N,24.19.

[2115] MS(EI): 346(M⁺).

[2116]¹ H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21-1.26(3H,m), 1.62-1.80(7H,m), 2.66-2.70(1H,m), 5.38(1H,s), 7.25(1H,s), 7.38(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.72(1H,brs), 12.15(1H,brs).

Example 324 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-cycloheptyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2117] The title compound was prepared from methyl cycloheptanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2118] MP: 228° C.

[2119] Anal. Calcd. for: C₂₀H₂₀N₆O:C,66.65;H,5.59;N,23.32.

[2120] Found: C,66.45;H,5.70;N,22.97.

[2121] MS(EI): 360(M⁺).

[2122]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.38-1.98(12H,m), 2.76-2.79(1H,m), 5.37(1H,s), 7.24(1H,s), 7.38(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,=9.0 Hz), 9.72(1H,brs), 12.13(1H,brs).

Example 325 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-cyclohexyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2123] The title compound was prepared from methyl cyclohexanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2124] MP: 193° C.

[2125] Anal. Calcd. for: C₂₀H₁₈BrN₅ 1/2 H₂O:C,57.56;H,4.59;N,16.78.

[2126] Found: C,57.25;H,4.37;N,16.56.

[2127] MS(EI): 408(M⁺).

[2128]¹ H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21-1.26(3H,m), 1.66-1.80(7H,m), 2.66-2.69(1H,m), 5.45(1H,s), 7.33(1H,s), 7.55-7.60(2H,m), 7.82(1H,d,J=7.3 Hz), 9.73(1H,brs), 12.24(1H,brs).

Example 326 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-cycloheptyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2129] The title compound was prepared from methyl cycloheptanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2130] MP: 252° C.

[2131] Anal. Calcd. for: C₂₁H₂₀BrN₅ 1/2 H₂O:C,58.48;H,4.91;N,16.24.

[2132] Found: C,58.53;H,4.73;N,16.19.

[2133] MS(EI): 422(M⁺).

[2134]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.44-1.58(12H,m), 2.76-2.79(1H,m), 5.44(1H,s), 7.31(1H,s), 7.54-7.60(2H,m), 7.83(1H,d,J=7.3 Hz), 9.73(1H,brs), 12.23(1H,brs).

Example 327 5-Cyano-4,7-dihydro-6-propyl-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2135] The title compound was prepared from methyl butyrate, pyridine-3-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2136] MP: 201° C.

[2137] Anal. Calcd. for: C₁₅H₁₅N₅:C,67.90;H,5.70;N,26.40.

[2138] Found: C,67.42;H,5.74;N,26.72.

[2139] MS(EI): 265(M⁺).

[2140]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.62-1.67(2H,m), 2.36-2.39(2H,m), 4.98(1H,s), 7.27(1H,s), 7.35(1H,dd,J=7.3 Hz and 2.9 Hz), 7.54(1H,d,J=7.3 Hz), 8.41-8.44(2H,m), 9.81(1H,brs), 12.18(1H,brs).

Example 328 3-t-Butoxycarbonyloxy-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-1 H-pyrazolo[3,4-b]pyridine

[2141] To a solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-3-hydroxy-6-propyl-2H-pyrazolo[3,4-b]pyridine (12.5 g) in THF (400 mL) was added triethylamine (4.5 g), dimethylaminopyridine (0.5 g) and di-t-butylcarbonate (9.6 g) and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (12 g) as colorless crystals.

[2142] MP: 182° C.

[2143] Anal. Calcd. for: C₂₁H₂₃ClN₄O₃:C,60.79;H,5.59;N,13.50.

[2144] Found: C,60.60;H,5.50;N,13.44.

[2145] MS(EI): 414(M⁺).

[2146]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.54(9H,s), 2.49-2.51(2H,m), 5.18(1H,s), 7.23-7.27(2H,m), 7.32(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 9.15(1H,brs), 10.99(1H,brs).

Example 329 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-(2,2-dimethoxyethyl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2147] The title compound was prepared from methyl 3,3-dimethoxypropionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2148] MP: 115° C.

[2149] Anal. Calcd. for: C₁₇H₁₆N₆O₃ 1.0 H₂O:C,55.13;H,4.90;N,22.69.

[2150] Found: C,55.30;H,4.51;N,22.99.

[2151] MS(EI): 352(M⁺).

[2152]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.71(2.75(2H,m), 3.28(3H,s), 3.31(3H,s), 4.74(1H,t,J=5.9 Hz), 5.43(1H,s), 7.28(1H,s), 7.40(1H,d,J=6.6 Hz), 7.61(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.99(1H,brs), 12.18(1H,brs).

Example 330 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-(2,2-dimethoxyethyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2153] The title compound was prepared from methyl 3,3-dimethoxypropionate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2154] MP: 180° C.

[2155] Anal. Calcd. for: C₂₀H₂₃ClN₄O₂:C,62.09;H,5.99;N,14.48.

[2156] Found: C,62.35;H,6.02;N,14.50.

[2157] MS(EI): 386(M⁺).

[2158]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.59-1.64(2H,m), 2.28-2.35(4H,m), 3.00(3H,s), 3.02(3H,s), 3.81(1H,t,J=7.3 Hz), 5.31(1H,s), 7.24-7.31(3H,m), 7.40(1H,d,J=7.3 Hz), 9.75(1H,brs), 11.92(1H,brs).

Example 331 4-(2,1-Benzoisoxazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2159] The title compound was prepared from methyl butyrate, 2,1-benzoisoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2160] MP: 239° C.

[2161] MS(EI): 305(M⁺).

[2162]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.64-1.67(2H,m), 2.40-2.43(2H,m), 5.23(1H,s), 6.91(1H,d,J=6.6 Hz), 7.28(1H,s), 7.36(1H,dd,J=9.3 Hz and 6.6 Hz), 7.52(1H,d,J=9.3 Hz), 9.37(1H,s), 9.96(1H,brs), 12.21(1H,brs).

Example 332 4-(2,1-Benzoisoxazol-4-yl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[2163] The title compound was prepared from methyl isobutyrate, 2,1-benzoisoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2164] MP: 245° C.

[2165] MS(EI): 305(M⁺).

[2166]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.23-1.26(6H,m), 3.03(1H,t,J=5.9 Hz), 5.21(1H,s), 6.92(1H,d,J=6.6 Hz), 7.30(1H,s), 7.37(1H,dd,J=9.3 Hz and 6.6 Hz), 7.53(1H,d,J=9.3 Hz), 9.34(1H,s), 9.78(1H,brs), 12.23(1H,brs).

Example 333 4-(2,1-Benzoisoxazol-4-yl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2167] The title compound was prepared from methyl cyclopropanecarboxylate, 2,1-benzoisoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2168] MP: 248° C.

[2169] MS(EI): 303(M⁺).

[2170]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.89-0.91(2H,m), 1.05-1.08(2H,m), 1.94-1.98(2H,m), 5.20(1H,s), 6.91(1H,d,J=6.6 Hz), 7.28(1H,s), 7.36(1H,dd,J=9.3 Hz and 6.6 Hz), 7.52(1H,d,J=9.3 Hz), 9.26(1H,s), 9.36(1H,brs), 12.22(1H,brs).

Example 334 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-6-(1-t-butoxycarbonylindol-3-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2171] The title compound was prepared from methyl 1-t-butoxycarbonylindole-3-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.

[2172] MP: 202° C.

[2173] MS(EI): 479(M⁺).

[2174]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.65(9H,s), 5.60(1H,s), 7.27-7.41(3H,m), 7.54-7.58(2H,m), 7.64(1H,dd,J=7.3 Hz and 7.2 Hz), 7.97(1H,d,J=7.3 Hz), 8.03(1H,s), 8.10(1H,d,J=7.3 Hz), 10.23(1H,brs), 12.26(1H,brs).

Example 335 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(indol-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2175] (1-t-Butoxycarbonylindol-3-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.6 g) was added to trifluoroacetic acid (15 mL) under ice-cooling and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to neutralize the mixture. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.4 g) as colorless crystals.

[2176] MP: 238° C.

[2177] Anal. Calcd. for: C₂₁H₁₃N₇O 3/5 H₂O:C,64.64;H,3.67;N,25.13.

[2178] Found: C,64.77;H,4.05;N,25.59.

[2179] MS(EI): 379(M⁺).

[2180]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.56(1H,s), 7.08(1H,dd,J=7.3 Hz and 7.2 Hz), 7.15(1H,dd,J=7.3 Hz and 7.2 Hz), 7.44(1H,s), 7.44-7.54(3H,m), 7.65(1H,dd,J=7.3 Hz and 7.2 Hz), 7.76(1H,s), 7.95(1H,d,J=7.3 Hz), 9.98(1H,brs), 11.63(1H,brs), 12.20(1H,brs).

Example 336 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-3-dimethoxymethyl-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2181] The title compound was prepared from methyl dimethylacetate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.

[2182] MP: 212° C.

[2183] Anal. Calcd. for: C₁₉H₂₁ClN₄O₂:C,61.21;H,5.68;N,15.03.

[2184] Found: C,61.25;H,5.69;N,15.17.

[2185] MS(EI): 372(M⁺).

[2186]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.88(3H,t,J=7.3 Hz), 1.57-1.63(2H,m), 2.28-2.35(2H,m), 2.93(6H,s), 4.93(1H,s), 5.30(1H,s), 7.10(1H,d,J=7.3 Hz), 7.19(1H,dd,J=7.3 Hz and 7.2 Hz), 7.25(1H,dd,J=7.3 Hz and 7.2 Hz), 7.35(1H,d,J=7.3 Hz), 9.80(1H,brs), 12.29(1H,brs).

Example 337 5-Cyano-4,7-dihydro-6-propyl-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2187] The title compound was prepared from methyl butyrate, pyridine-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2188] MP: 224° C.

[2189] Anal. Calcd. for: C₁₅H₁₅N₅:C,67.90;H,5.70;N,26.40.

[2190] Found: C,67.90;H,5.79;N,26.31.

[2191] MS(EI): 265(M⁺).

[2192]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.62-1.67(2H,m), 2.35-2.43(2H,m), 4.95(1H,s), 7.20(2H,dd,J=4.6 Hz and 1.5 Hz), 7.29(1H,s), 8.50(2H,dd,J=4.6 Hz and 1.5 Hz), 9.84(1H,brs), 12.20(1H,brs).

Example 338 5-Cyano-4,7-dihydro-4-(3-methyl-2-nitrophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2193] The title compound was prepared from methyl butyrate, 3-methyl-2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2194] MP: 250° C.

[2195] Anal. Calcd. for: C₁₇H₁₇N₅O₂:C,63.15;H,5.30;N,21.66.

[2196] Found: C,62.89;H,5.51;N,22.11.

[2197] MS(EI): 323(M⁺).

[2198]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.94(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 2.26(3H,s), 2.36-2.42(2H,m), 4.83(1H,s), 7.17(1H,s), 7.20(1H,d,J=7.3 H), 7.32(1H,d,J=7.3 Hz), 7.48(1H,dd,J=7.3 Hz and 7.2 Hz), 9.91(1H,brs), 12.22(1H,brs).

Example 339 5-Cyano-4,7-dihydro-4-(3-methyl-2-nitrophenyl)-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[2199] The title compound was prepared from methyl isobutyrate, 3-methyl-2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2200] MP: 261° C.

[2201] Anal. Calcd. for: C₁₇H₁₇N₅O₂ 1/2 H₂O:C,61.43;H,5.46;N,21.07.

[2202] Found: C,61.82;H,5.32;N,21.31.

[2203] MS(EI): 323(M⁺).

[2204]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.21(3H,d,J=7.2 Hz), 1.26(3H,d,J=7.2 Hz), 2.25(3H,s), 3.01(1H,t,J=7.2 Hz), 4.84(1H,s), 7.17(1H,s), 7.22(1H,d,J=7.3 Hz), 7.32(1H,d,J=7.3 Hz), 7.48(1H,dd,J=7.3 Hz and 7.2 Hz), 9.71(1H,brs), 12.24(1H,brs).

Example 340 5-Cyano-6-cyclopropyl-4,7-dihydro-4-(3-methyl-2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[2205] The title compound was prepared from methyl cyclopropanecarboxylate, 3-methyl-2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2206] MP: 265° C.

[2207] Anal. Calcd. for: C₁₇H₁₅N₅O₂:C,63.54;H,4.71;N,21.79.

[2208] Found: C,63.44;H,4.85;N,22.04.

[2209] MS(EI): 321(M⁺).

[2210]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.90-1.07(4H,m), 1.96-1.99(1H,m), 2.26(3H,s), 4.81(1H,s), 7.17(1H,s), 7.20(1H,d,J=7.3 Hz), 7.32(1H,d,J=7.3 Hz), 7.48(1H,dd,J=7.3 Hz and 7.2 Hz), 9.23(1H,brs), 12.23(1H,brs).

Example 341 Ethyl 4-(2,1,3-benzoxazol-4-yl)-4,7-dihydro-6-(1-methylethyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 1/2 ethyl acetate

[2211] The title compound was prepared from 2,1,3-benzoxazole-4-aldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.

[2212] MP: 190-193° C. (decomposition)

[2213]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.73(3H,t,J=7.1 Hz), 1.19(3H,d,J=7.1 Hz), 1.29(3H,d,J=7.1 Hz), 3.77(2H,m), 4.37(1H,m), 5.69(1H,s), 7.12(1H,d,J=6.6 Hz), 7.22(1H,s), 7.51(1H,dd,J=6.6,9.0 Hz), 7.78(1H,d,J=8.8 Hz), 9.31(1H,brs), 12.02(1H,brs).

Example 342 Ethyl 4-(2-nitrophenyl)-4,7-dihydro-6-(1-methylethyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2214] The title compound was prepared from 2-nitrobenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.

[2215] MP: 205-206° C.

[2216]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.78(3H,t,J=6.8 Hz), 1.15(3H,d,J=7.1 Hz), 1.26(3H,d,J=7.1 Hz), 3.71(2H,m), 4.33(1H,m), 5.44(1H,s), 7.29-7.34(3H,m), 7.58(1H,m), 7.78(1H,d,J=8.0 Hz), 9.33(1H,brs), 12.11(1H,brs).

Example 343 Ethyl 4-(2-methoxyphenyl)-4,7-dihydro-6-(1-methylethyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 1/2 Ethyl Acetate

[2217] The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.

[2218] MP: 179-180° C.

[2219]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.81(3H,t,J=7.1 Hz), 1.17(3H,d,J=7.1 Hz), 1.27(3H,d,J=7.1 Hz), 3.76(2H,m), 3.85(3H,s), 4.31(1H,m), 5.46(1H,s), 6.77(1H,m), 6.89(1H,d,J=8.0 Hz), 6.94(1H,d,J=7.6 Hz), 7.04(1H,m), 7.14(1H,s), 8.98(1H,brs), 11.86(1H,brs)

Example 344 Ethyl 4-(2-bromophenyl)-4,7-dihydro-6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2220] The title compound was prepared from cyclopropanecarbonyl chloride, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 277.

[2221] MP: 168-170° C.

[2222]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.1 Hz), 0.87-0.90(2H,m), 1.10-1.14(2H,m), 3.16(1H,m), 3.78(2H,m), 5.57(1H,s), 7.01(1H,dd,J=5.8,7.6 Hz), 7.09(1H,d,J=7.8 Hz), 7.24(1H,m), 7.29(1H,s), 7.51(1H,d,J=6.8 Hz), 8.65(1H,brs), 12.01(1H,brs).

Example 345 Ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2223] The title compound was prepared from cyclopropanecarbonyl chloride, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 277.

[2224] MP: 168-170° C.

[2225]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(3H,t,J=7.1 Hz), 0.88-1.00(2H,m), 1.10-1.18(2H,m), 3.14(1H,m), 3.80(2H,m), 5.64(1H,s), 7.33(1H,s), 7.34-7.49(2H,m), 7.68(1H,m), 8.77(1H,brs), 12.10(1H,brs).

Example 346 4-(2-Chlorophenyl)-5-cyano-7-methyl-6-propyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2226] A solution of 3-aminopyrazole (3.0 g), di-t-butyl dicarbonate (17.3 g) and dimethylaminopyridine (1.3 g) in tetrahydrofuran (360 ml) was stirred at room temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a mixture (7.9 g) of 1-(t-butoxycarbonyl)-3-(t-butoxycarbonylamino)pyrazole and 2-(t-butoxycarbonyl)-3-(t-butoxycarbonylamino)pyrazole as a white amorphous solid. To a suspension of the obtained white amorphous solid (7.9 g) and sodium hydride (1.1 g) in DMF (80 ml) was added methyl iodide (4.0 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water under ice-cooling and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a white solid (5.3 g). The obtained white solid (5.3 g) was dissolved in methylene chloride (50 ml), and trifluoroacetic acid (7 ml) was added. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol (10:1)) to give 3-methylaminopyrazole (1.54 g) as a colorless transparent oil. Subsequently, the title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 3-methylaminopyrazole in the same manner as in Example 94.

[2227] MP: 170-171° C.

[2228] Anal. Calcd. for: C₁₇H₁₇N₄Cl: C,65.28;H,5.48;N,17.91.

[2229] Found: C,65.14;H,5.52;N,17.72.

[2230] MS(EI): 312(M⁺).

[2231]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.00(3H,t,J=7.3 Hz), 1.68(2H,m), 2.62(2H,m), 3.36(3H,s), 5.36(1H,s), 7.22-7.26(2H,m), 7.30-7.32(2H,m), 7.42(1H,d,J=8.1 Hz), 12.31(1H,brs).

Example 347 4-(2,1,3-Benzoxazol-4-yl)-5-cyano-7-methyl-6-propyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2232] The title compound was prepared from methyl butyrate, 2,1,3-benzoxazole-4-aldehyde and 3-methylaminopyrazole in the same manner as in Example 346.

[2233] MP: 198-200° C.

[2234] Anal. Calcd. for: C₁₇H₁₆N₆O: C,63.74;H,5.03;N,26.23.

[2235] Found: C,63.78;H,5.12;N,26.47.

[2236] MS(EI): 320(M⁺).

[2237]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.97(3H,t,J=7.4 Hz), 1.61(2H,m), 2.63(2H,m), 3.41(3H,s), 5.40(1H,s), 7.32(1H,s), 7.40(1H,d,J=6.6 Hz), 7.59(1H,dd,J=6.5,6.6 Hz), 7.92(1H,d,J=9.3 Hz), 12.30(1H,brs).

Example 348 4-(2-Bromo-3-cyanophenyl)-5-cyano-7-methyl-6-propyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2238] The title compound was prepared from methyl butyrate, 2-bromo-3-cyanobenzaldehyde and 3-methylaminopyrazole in the same manner as in Example 346.

[2239] MP: 218-220° C.

[2240] Anal. Calcd. for: C₁₈H₁₆N₅Br: C,56.56;H,4.22;N,18.32.

[2241] Found: C,56.60;H,4.41;N,18.18.

[2242] MS(EI): 382(M⁺).

[2243]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.00(3H,t,J=7.3 Hz), 1.63(2H,m), 2.62(2H,m), 3.37(3H,s), 5.47(1H,s), 7.39(1H,s), 7.56-7.58(2H,m), 7.83(1H,m), 12.41(1H,brs).

Example 349 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine

[2244] The title compound was prepared from ethyl acetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2245]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.14(3H,s), 5.35(1H,s), 7.21-7.33(4H,m), 7.42(1H,d,J=8.1 Hz), 9.87(1H,brs), 12.15(1H,brs).

Example 350 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine Dihydrochloride

[2246] A solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals.

[2247] MP: 210-214° C. (decomposition).

[2248]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.20-3.40(3H,m), 3.84-4.00(3H,m), 4.17-4.40(4H,m), 5.49(1H,s), 7.26-7.37(4H,s), 7.45(1H,d,J=7.8 Hz), 10.22(1H,brs), 11.05(1H,brs), 12.33(1H,brs).

Example 351 6-Benzyloxymethyl-4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2249] The title compound was prepared from ethyl benzyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2250] MP: 165-166° C.

[2251]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 4.35(2H,d,J=2.9 Hz), 4.57(2H,s), 5.42(1H,s), 7.24-7.45(10H,m), 10.03(1H,brs), 12.22(1H,brs).

Example 352 4-.(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(methylpiperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine Dihydrochloride

[2252] 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo [3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals.

[2253] MP: 222-225° C. (decomposition).

[2254]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.66-2.75(2H,m), 2.75(3H,s), 3.00-3.10(4H,m), 3.41-3.55(4H,m), 5.42(1H,s), 7.24-7.36(4H,m), 7.43(1H,d,J=8.0 Hz), 9.77(1H,brs), 12.17(1H,brs).

Example 353 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2255] The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and piperidine in the same manner as in Example 352.

[2256]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.43(1H,m), 1.67-1.82(5H,m), 3.05-3.25(2H,m), 3.48(2H,m), 4.10(2H,m), 5.49(1H,s), 7.26-7.35(4H,m), 7.45(1H,d,J=8.0 Hz), 10.28(1H,brs), 10.59(1H,brs).

Example 354 Ethyl 4-(2-nitrophenyl)-4,7-dihydro-6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2257] The title compound was prepared from cyclopropanecarbonyl chloride, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 277.

[2258] MP: 162-164° C. (decomposition)

[2259]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.81(3H,t,J=7.4 Hz), 0.85-0.95(2H,m), 1.10-1.18(2H,m), 3.12(1H,m), 3.72(2H,m), 5.46(1H,s), 7.27-7.34(3H,m), 7.58(1H,m), 7.78(1H,d,J=8.0 Hz), 8.78(1H,brs), 12.12(1H,brs).

Example 355 Ethyl 4-(2,1,3-benzoxazol-4-yl)-4,7-dihydro-6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2260] The title compound was prepared from cyclopropanecarbonyl chloride, 2,1,3-benzoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 277.

[2261] MP: 109-111° C. (decomposition).

[2262]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.76(3H,t,J=6.8 Hz), 0.85-0.86(2H,m), 1.14-1.18(2H,m), 3.12(1H,m), 3.80(2H,m), 5.69(1H,s), 7.13(1H,d,J=6.6 Hz), 7.23(1H,s), 7.51(1H,m), 7.79(1H,d,J=9.0 Hz), 8.83(1H,brs), 12.05(1H,brs).

Example 356 4-(2,1,3-Benzoxazol-4-yl)-5-cyano-4,7-dihydro-2-(phenylcarbamoyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2263] The title compound was obtained as colorless crystals from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and phenylisocyanate in the same manner as in Example 204.

[2264] MS(EI): 425(M⁺).

[2265]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.64(2H,m), 2.58(2H,m), 5.44(1H,s), 7.10(1H,dd,J=6.3 and 7.6 Hz), 7.31-7.34(2H,m), 7.52(1H,d,J=6.6 Hz), 7.59-7.64(3H,m), 7.95(1H,s), 7.97(1H,d,J=9.0 Hz), 9.83(1H,brs), 10.30(1H,brs).

Example 357 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-1-(4-pentenoyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine

[2266] The title compound was obtained as colorless crystals from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and 4-pentenoyl chloride in the same manner as in Example 204.

[2267] MP: 140° C.

[2268] Anal. Calcd. for: C₂₁H₂₁ClN₄O:C,66.22;H,5.62;N,14.71.

[2269] Found: C,66.20;H,5.60;N,14.65.

[2270] MS(EI): 380(M⁺).

[2271]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.62(2H,m), 2.39-2.58(4H,m), 3.11(2H,t,J=7.6 Hz), 4.98(1H,d,J=7.1 Hz), 5.06(1H,d,J=10.3 Hz), 5.40(1H,s), 5.85(1H,m), 7.27-7.37(4H,m), 7.46(1H,d,J=7.0 Hz), 9.58(1H,brs).

Example 358 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-2-(4-pentenoyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2272] The title compound was obtained as colorless crystals from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, dimethylaminopyridine and 4-pentenoyl chloride in the same manner as in Example 204.

[2273] MP: 176-177° C.

[2274] Anal. Calcd. for: C₂₁H₂₁ClN₄O:C,66.22;H,5.56N,14.71.

[2275] Found: C,66.15;H,5.63;N,14.55.

[2276] MS(EI): 380(M⁺).

[2277]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.3 Hz), 1.67(2H,m), 2.34-2.49(4H,m), 3.00(2H,t,J=7.6 Hz), 4.96(1H,d,J=10.6 Hz), 5.02(1H,d,J=27.1 Hz), 5.36(1H,s), 5.82(1H,m), 7.30-7.35(3H,m), 7.46(1H,d,J=7.8 Hz), 7.83(1H,s), 10.39(1H,brs).

Example 359 5-Cyano-4,7-dihydro-4-(6-methylpyridin-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2278] The title compound was prepared from methyl butyrate, 6-methylpyridine-2-aldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2279] MP: 177-181° C.

[2280] Anal. Calcd. for: C₁₆H₁₇N₅ 4/5 H₂O:C,65.42;H,6.38;N,23.84.

[2281] Found: C,65.52;H,6.31;N,24.19.

[2282] MS(EI): 279(M⁺).

[2283]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.95(3H,t,J=7.6 Hz), 1.66(2H,m), 2.41(2H,m), 2.43(3H,s), 4.94(1H,s), 6.98(1H,d,J=7.6 Hz), 7.06(1H,d,J=7.5 Hz), 7.21(1H,s), 7.62(1H,dd,J=7.6 and 7.7 Hz), 9.71(1H,brs), 12.09(1H,brs).

Example 360 4-(5-Cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine)pyridine-N-oxide

[2284] The title compound was prepared from methyl butyrate, pyridine-4-aldehyde-N-oxide and 3-aminopyrazole in the same manner as in Example 94.

[2285] MP: 110-115° C.

[2286] Anal. Calcd. for: C₁₅H₁₅N₅O:C,62.01 ;H,6.18;N,24.11.

[2287] Found: C,61.94;H,5.85;N,23.73.

[2288] MS(EI): 283(M⁺).

[2289]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.62(2H,m), 2.36(2H,m), 4.98(1H,s), 7.18(2H,d,J=6.6 Hz), 7.31(1H,s), 8.14(2H,d,J=6.3 Hz), 9.86(1H,brs), 12.2(1H,brs).

Example 361 5-Cyano-4,7-dihydro-4-(3-(4-morpholinomethyl)phenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2290] The title compound was prepared from methyl butyrate, 3-(4-morpholinomethyl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2291] MS(EI): 363(M⁺).

[2292]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.63(2H,m), 2.30(4H,m), 2.30(2H,m), 3.40(2H,s), 3.53(4H,m), 4.86(1H,s), 7.05(1H,d,J=7.8 Hz), 7.10(1H,d,J=7.6 Hz), 7.14(1H,s), 7.19(1H,s), 7.23(1H,dd,J=7.5 and 7.6 Hz), 9.70(1H,brs), 12.10(1H,brs).

Example 362 4-(3-Bromophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2293] The title compound was prepared from methyl butyrate, 3-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2294] MP: 202-205° C.

[2295] Anal. Calcd. for: C₁₆H₁₅BrN₄:C,55.99;H,4.41;N,16.32.

[2296] Found: C,55.82;H,4.46;N,17.03.

[2297] MS(EI): 343(M⁺).

[2298]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.91(3H,t,J=7.3 Hz), 1.63(2H,m), 2.37(2H,m), 4.92(1H,s), 7.18(1H,d,J=7.9 Hz), 7.25(1H,s), 7.28(1H,d,J=7.8 Hz), 7.33(1H,s), 7.39(1H,d,J=8.3 Hz), 9.80(1H,brs), 12.18(1H,brs).

Example 363 5-Cyano-4,7-dihydro-4-(4-fluoro-2-chlorophenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2299] The title compound was prepared from methyl butyrate, 2-chloro-4-fluorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2300] MP: 209-212° C.

[2301] Anal. Calcd. for: C₁₆H₁₄ClFN₄:C,60.67;H,4.45;N,17.69.

[2302] Found: C,60.48;H,4.48;N,17.87.

[2303] MS(EI): 316(M⁺).

[2304]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.3 Hz), 1.64(2H,m), 2.39(2H,m), 5.33(1H,s), 7.17-7.40(3H,m), 7.41(1H,dd,J=2.7 and 6.1 Hz), 9.85(1H,brs), 12.17(1H,brs).

Example 364 5-Cyano-4,7-dihydro-4-(3-(morpholin-4-yl)phenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2305] The title compound was prepared from methyl butyrate, 3-(morpholin-4-yl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2306] MP: 196-200° C.

[2307] Anal. Calcd. for: C₂₀H₂₃N₅O:C,68.47;H,6.63;N,20.04.

[2308] Found: C,68.41;H,6.77;N,20.16.

[2309] MS(EI): 349(M⁺).

[2310]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.92(3H,t,J=7.3 Hz), 1.63(2H,m), 2.32(2H,m), 3.05(4H,t,J=4.6 Hz), 7.71(4H,t,J=4.6 Hz), 4.80(1H,s), 6.59(1H,d,J=7.5 Hz), 6.74(1H,m), 6.76(1H,s), 7.13(1H,dd,J=7.8 and 7.8 Hz), 7.21(1H,s), 9.67(1H,brs), 12.02(1H,brs).

Example 365 5-Cyano-4,7-dihydro-4-(3-(morpholin-4-yl)phenyl)-6-isopropyl-2H-pyrazolo[3,4-b]pyridine

[2311] The title compound was prepared from methyl isobutyrate, 3-(morpholin-4-yl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2312] MP: 254-257° C.

[2313] Anal. Calcd. for: C₂₀H₂₃N₅O:C,68.47;H,6.63;N,20.04.

[2314] Found: C,68.56;H,6.73;N,20.30.

[2315] MS(EI): 349(M⁺).

[2316]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.20(3H,d,J=7.0 Hz), 1.22(3H,d,J=7.1 Hz), 3.02(2H,m), 3.04(4H,t,J=4.8 Hz), 3.70(4H,t,J=4.8 Hz), 4.78(1H,s), 6.59(1H,d,J=7.6 Hz), 7.74(1H,s), 7.13(1H,dd,J=7.5 and 8.1 Hz), 7.22(1H,s), 9.48(1H,brs), 12.09(1H,brs).

Example 366 5-Cyano-6-cyclopropyl-4,7-dihydro-4-(3-(morpholin-4-yl)phenyl)-2H-pyrazolo[3,4-b]pyridine

[2317] The title compound was prepared from methyl cyclopropanecarboxylate, 3-(morpholin-4-yl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.

[2318] MP: >260° C.

[2319] MS(EI): 347(M⁺).

[2320]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.86(4H,m), 1.93-1.98(1H,m), 3.05(4H,t,J=4.6 Hz), 3.70(4H,t,J=4.6 Hz), 4.79(1H,s), 6.56(1H,d,J=7.5 Hz), 6.74(1H,s), 6.77(1H,s), 7.13(1H,dd,J=7.8 and 7.8 Hz), 7.20(1H,s), 8.98(1H,brs), 12.09(1H,brs).

[2321] The compounds of the above-described Examples are as follows.

Example 1001 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2322] To a solution of ethyl isonipecotate (10.0 g) in THF (200 mL) was added triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di-tert-butyldicarbonate (15.3 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. To a solution of acetonitrile (3.2 g) in THF (300 mL) was added n-BuLi (44 mmol) at −78° C. and stirred for three hours. Further, ethyl N-Boc-piperidine-4-carboxylate (16.3 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 1-(N-Boc-piperidin-4-yl)-2-cyanoethan-1-one (11.6 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2-(N-Boc-piperidin-4-yl)-1-cyanoethan-2-one (1.7 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.

[2323] MP: 226° C.

[2324] Anal. Calcd. For: C₂₃H₂₅N₇O₃:C,61.73; H,5.63;N,21.97.

[2325] Found: C,61.45;H,5.82;N,21.61.

[2326] MS(EI): 447(M⁺).

[2327]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.42(9H,m), 1.59-1.62(2H,m), 1.89-1.92(2H,m), 2.62-2.86(3H,m), 4.05-4.08(2H,m), 5.40(1H,s), 7.26(1H,s), 7.41(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.81(1H,brs), 12.24(1H,brs).

Example 1002 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2328] 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.7 g) was added to trifluoroacetic acid (20 mL) at 0° C. and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.83 g) as yellow crystals.

[2329] MP: 216° C.

[2330] MS(EI): 348(M⁺).

[2331]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.78-1.81(2H,m), 2.07-2.11(2H,m), 2.80-2.86(3H,m), 3.27-3.30(3H,m), 5.39(1H,s), 7.27(1H,s), 7.43(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.86(1H,brs), 12.24(1H,brs).

Example 1003 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2332] To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (0.7 g) in MeOH (200 mL) was added 37% formaldehyde (0.18 g), sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) at room temperature and the mixture was stirred overnight. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals.

[2333] MP: >270° C.

[2334] MS(EI): 361(M⁺).

[2335]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.57-1.60(2H,m), 1.82-1.88(2H,m), 2.01-2.06(2H,m), 2.15(3H,s), 2.58-2.61(1H,m), 2.85-2.88(2H,m), 5.40(1H,s), 7.26(1H,s), 7.40(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.76(1H,brs), 12.17(1H,brs).

Example 1004 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2336] The title compound was prepared from ethyl nipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2337] MP: 229° C.

[2338] Anal. Calcd. For: C₂₃H₂₅N₇O₃:C, 61.73;H,5.63;N,21.97.

[2339] Found: C,61.56;H,5.66;N,21.67.

[2340] MS(EI): 447(M⁺).

[2341]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.32-1.40(2H,m), 1.39(9H,s), 1.69-1.78(2H,m), 2.69-2.76(2H,m), 3.16-3.19(1H,m), 3.92-3.95(2H,m), 5.42(1H,s), 7.28(1H,s), 7.42(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.87(1H,brs), 12.21(1H,brs).

Example 1005 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2342] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2343] MP: 202° C.

[2344] Anal. Calcd. For: C₁₈H₁₇N₇O:C,62.24;H,4.93;N,28.23.

[2345] Found: C,61.97;H,5.13;N,27.89.

[2346] MS(EI): 347(M⁺).

[2347]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.42-1.45(1H,m), 1.72-1.88(3H,m), 2.66-2.84(5H,m), 2.94-3.02(1H,m), 5.38(1H,s), 7.26(1H,s), 7.39(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 10.39(1H,brs), 12.17(1H,brs).

Example 1006 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2348] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2349] MP: 228° C.

[2350] MS(EI): 361(M⁺).

[2351]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.53-1.76(4H,m), 2.21(3H,s), 2.47-2.55(4H,m), 2.93-2.96(1H,m), 5.38(1H,s), 7.27(1H,s), 7.40(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 10.16(1H,brs), 12.20(1H,brs).

Example 1007 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2352] The title compound was prepared from ethyl pipecolinate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2353] MS(EI): 447(M⁺).

[2354]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.27 and 1.32(9H,s), 1.42-1.97(6H,m), 3.30-3.33(1H,m), 3.53-3.61(1H,m), 4.47-4.50(1H,m), 5.37 and 5.39(1H,s), 7.26 and 7.29(1H,s), 7.38-7.44(1H,m), 7.54-7.60(1H,m), 7.90-7.93(1H,m), 9.63 and 9.73(1H,brs), 12.16(1H,brs).

Example 1008 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[2355] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2356] MS(EI): 347(M⁺).

[2357]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.27-1.88(6H,m), 3.12-3.16(1H,m), 4.12-4.15(1H,m), 4.48-4.58(1H,m), 5.64 and 5.66(1H,s), 7.22-7.28(1H,m), 7.45-7.52(2H,m), 7.87-7.90(1H,m), 8.26(1H,br), 10.92 and 10.94(1H,brs), 12.35(1H,brs).

Example 1009 4-(2,1,3-Benzoxadiazol-4-yl)-6-(4-t-butoxycarbonylmorpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2358] The title compound was prepared from ethyl morpholine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-amino-pyrazole in the same manner as in Example 1001.

[2359] MS(EI): 449(M⁺).

[2360]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.36 and 1.40(9H,s), 2.95-3.06(2H,m), 3.50-3.52(1H,m), 3.75-3.95(3H,m), 4.34-4.40(1H,m), 5.44 and 5.48(1H,s), 7.26 and 7.30(1H,s), 7.42-7.45(1H,m), 7.57-7.62(1H,m), 7.93-7.96(1H,m), 9.84 and 9.92(1H,brs), 12.23(1H,brs).

Example 1010 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[2361] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(4-t-butoxycarbonylmorpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2362] MS(EI): 349(M⁺).

[2363]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.64-2.95(4H,m), 3.53(1H,br), 3.55-3.57(1H,m), 3.82-3.85(1H,m), 4.41-4.45(1H,m), 5.43 and 5.44(1H,s), 7.24 and 7.28(1H,s), 7.38-7.41(1H,m), 7.56-7.61(1H,m), 7.91-7.94(1H,m), 9.74 and 9.76(1H,brs), 12.19(1H,brs).

Example 1011 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[2364] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2365] MP: 143° C.

[2366] MS(EI): 363(M⁺).

[2367]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.21(3H,s), 2.19-2.30(2H,m), 2.60-2.69(2H,m), 3.60-3.62(1H,m), 3.88-3.92(1H,m), 4.48-4.50(1H,m), 5.44(1H,s), 7.28(1H,s), 7.39(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.80(1H,brs), 12.20(1H,brs).

Example 1012 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2368] The title compound was prepared from ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2369] MP: 222° C.

[2370] MS(EI): 445(M⁺).

[2371]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41(9H,s), 2.35-2.39(2H,m), 3.46-3.48(2H,m), 3.90-3.92(2H,m), 5.43(1H,s), 6.06-6.09(1H,m), 7.28(1H,s), 7.45(1H,d,J=6.6 Hz), 7.60(1H,dd,J=9.0 Hz and 6.6 Hz), 7.93(1H,d,J=9.0 Hz), 9.94(1H,brs), 12.19(1H,brs).

Example 1013 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2372] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2373] MP: 180° C.

[2374] MS(EI): 345(M⁺).

[2375]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.26-2.32(2H,m), 2.87-2.90(2H,m), 3.30-3.36(3H,m), 5.42(1H,s), 6.09-6.10(1H,m), 7.30(1H,s), 7.43(1H,d,J=6.6 Hz), 7.60(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.87(1H,brs), 12.18(1H,brs).

Example 1014 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2376] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2377] MP: 218° C.

[2378] MS(EI): 359(M⁺).

[2379]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.24(3H,s), 2.35-2.42(2H,m), 2.91-2.93(2H,m), 3.31-3.33(2H,m), 5.42(1H,s), 6.04-6.05(1H,m), 7.27(1H,s), 7.43(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.87(1H,brs), 12.17(1H,brs).

Example 1015 4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-(N-t-butoxycarbonyl-N-methylamino)ethyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine

[2380] To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di-tert-butyldicarbonate (30 g) at 0° C. and the mixture was stirred at 40° C. for four hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-3-aminopropionate (16.7 g) as a colorless oil. To a solution of ethyl N-Boc-3-aminopropionate (5.0 g) in THF (50 mL) was added t-BuOK (2.8 g) and methyl iodide (4.9 g) at 0° C. and the mixture was stirred at room temperature for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 3-(N-Boc-N-methylamino)propionate (4.3 g) as a colorless oil. Subsequently, the title compound was prepared from ethyl 3-(N-Boc-N-methylamino)propionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2381] MP: 240° C.

[2382] Anal. Calcd. For: C₂₁H₂₃N₇O₃:C,59.85;H,5.50;N,23.26.

[2383] Found: C,59.69;H,5.45;N,23.22.

[2384] MS(EI): 421(M⁺).

[2385]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.26 and 2.32(9H,s), 2.62-2.63(2H,m), 2.81(3H,s), 3.48-3.55(2H,m), 5.40(1H,s), 7.27(1H,s), 7.40(1H,d,J=6.6 Hz), 7.57(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 10.07(1H,brs), 12.15(1H,brs).

Example 1016 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-(N-methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine

[2386] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(2-(N-t-butoxycarbonyl-N-methylamino)ethyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2387] MP: 174° C.

[2388] MS(EI): 321(M⁺).

[2389]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.29(3H,s), 2.50-2.78(4H,m), 3.31(3H,br), 5.39(1H,s), 7.24(1H,s), 7.43(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz).

Example 1017 4-(2,1,3-Benzoxadiazol-4-yl)-6-(2-(N-t-butoxycarbonyl-amino)ethyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2390] The title compound was prepared from ethyl 3-aminopropionate hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2391] MP: 231° C.

[2392] Anal. Calcd. For: C₂₀H₂₁N₇O₃:C,58.96;H,5.20;N,24.06.

[2393] Found: C,58.81;H,5.19;N,23.82.

[2394] MS(EI): 407(M⁺).

[2395]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.33(9H,s), 2.55-2.60(2H,m), 3.23-3.33(2H,m), 5.41(1H,s), 6.81(1H,brs), 7.25(1H,s), 7.44(1H,d,J=6.6 Hz), 7.57(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.94(1H,brs), 12.14(1H,brs).

Example 1018 6-(2-Aminoethyl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2396] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(2-(N-t-butoxycarbonylamino)ethyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2397] MS(EI): 307(M⁺).

[2398]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.50-2.54(2H,m), 2.88(2H,t,J=7.3 Hz), 3.35(4H,br), 5.40(1H,s), 7.25(1H,s), 7.44(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz).

Example 1019 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-(N,N-dimethylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine

[2399] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(2-(N-methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2400] MP: 215° C.

[2401] MS(EI): 335(M⁺).

[2402]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.19(6H,s), 2.45-2.62(4H,m), 5.41(1H,s), 7.27(1H,s), 7.43(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 10.04(1H,brs), 12.16(1H,brs).

Example 1020 4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-t-butoxycarbonyl-N-methylamino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine

[2403] The title compound was prepared from glycine ethyl ester hydrochloride, 2,1,3-benzoxadiazole-4-aldehyde and 3-amino-pyrazole in the same manner as in Example 1015.

[2404] MP: 207° C.

[2405] Anal. Calcd. For: C₂₀H₂₁N₇O₃:C,58.96;H,5.20;N,24.06.

[2406] Found: C,58.80;H,5.12;N,24.38.

[2407] MS(EI): 407(M⁺).

[2408]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.33 and 1.39(9H,s), 2.81(3H,s), 4.13-4.20(2H,m), 5.42(1H,s), 7.29(1H,s), 7.43(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.94(1H,d,J=9.0 Hz), 9.33(1H,brs), 12.15(1H,brs).

Example 1021 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-((N-methylamino)methyl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate

[2409] 4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-t-butoxycarbonyl-N-methylamino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine (0.6 g) was added to trifluoroacetic acid (10 mL) at 0° C. and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure and the residue was crystallized by ethanol, and the precipitated crystals were collected by filtration to give the title compound (0.1 g) as yellow crystals.

[2410] MP: 174° C.

[2411] MS(EI): 307(M⁺).

[2412]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.10(3H,s), 4.51-4.68(2H,m), 7.24(1H,d,J=6.6 Hz), 7.45(1H,s), 7.52(1H,dd,J=9.0 Hz and 6.6 Hz), 7.89(1H,d,J=9.0 Hz), 8.08-8.20(2H,br), 10.81(1H,brs), 12.41(1H,brs).

Example 1022 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N-methylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine

[2413] The title compound was prepared from ethyl 4-aminocyclo-hexanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1015, and Example 1002 followed.

[2414] MS(EI): 375(M⁺).

[2415]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.32-1.35(2H,m), 1.81-2.12(6H,m), 2.57(3H,s), 2.65-2.69(1H,m), 2.81-2.85(1H,m), 5.39 (1H,s), 7.28(1H,s), 7.41(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 8.54(1H,br), 9.79(1H,brs), 12.22(1H,brs).

Example 1023 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N,N-dimethylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine

[2416] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N-methylamino)-cyclohexyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2417] MP: 241° C.

[2418] MS(EI): 389(M⁺).

[2419]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.15-2.02(9H,m), 2.15 and 2.21(6H,s), 2.62-2.76(1H,m), 5.38 and 5.43(1H,s), .7.26(1H,s), 7.38-7.44(1H,m), 7.56-7.62(1H,m), 7.90-7.96(1H,m), 9.74(1H,brs), 12.18(1H,brs).

Example 1024 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-phenylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2420] To a solution of ethyl isonipecotate (8.9 g) in CH₂Cl₂ (500 mL) was added triphenyl bismus (25 g) and Copper(II)acetate (10.3 g) at room temperature, the mixture was stirred overnight. After filteration, the mixture was extracted with CH₂Cl₂. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as colorless crystals. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-BuLi (41 mmol) at −78° C. Further, ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (2.0 g) as colorless crystals. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (0.5 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.

[2421] MS(FAB): 424(M⁺+1).

[2422]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.73-1.76(2H,m), 2.14-2.18(2H,m), 2.62-2.66(2H,m), 2.81-2.84(1H,m), 3.80-3.84(2H,m), 5.41(1H,s), 6.75(1H,dd,J=7.3 Hz and 7.2 Hz), 6.94-6.96(2H,m), 7.18-7.27(3H,m), 7.42(1H,d,J=6.6 Hz), 7.59 (1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.81(1H,brs), 12.17(1H,brs).

Example 1025 6-(1-Acetylpiperidin-4-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2423] To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.

[2424] MP: 248° C.

[2425] MS(FAB): 340(M⁺+1).

[2426]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.62-1.64(2H,m), 1.82-1.84 (1H,m), 2.00-2.02(4H,m), 2.49-2.50(1H,m), 2.94-3.07(2H,m), 3.89-3.92(1H,m), 4.48-4.51(1H,m), 5.40(1H,s), 7.27(1H,s), 7.42(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.81(1H,brs), 12.18(1H,brs).

Example 1026 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-benzoylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2427] The title compound was prepared from benzoylchloride, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2428] MP: 228° C.

[2429] MS(FAB):452(M⁺+1).

[2430]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.59-1.76(2H,m), 2.04-2.08 (2H,m), 2.76-2.80(1H,m), 3.01-3.09(2H,m), 3.58-3.60(1H,m), 4.60-4.63(1H,m), 5.41(1H,s), 7.28(1H,s), 7.43-7.46(6H,m), 7.56-7.59(1H,m), 7.92(1H,d,J=9.0 Hz), 9.90(1H,brs), 12.21(1H,brs).

Example 1027 6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine

[2431] The title compound was prepared from acetyl chloride, ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2432] MP: 237° C.

[2433] MS(EI): 387(M⁺).

[2434]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.00 and 2.04(3H,s), 2.46-2.49(2H,m), 3.55-3.58(2H,m), 4.00-4.06(2H,m), 5.44(1H,s), 6.10(1H,s), 7.29(1H,s), 7.45(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.93(1H,d,J=9.0 Hz), 9.94(1H,brs), 12.17(1H,brs).

Example 1028 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-(ethoxycarbonyl)piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2435] The title compound was prepared from ethyl chloroformate, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example. 1025.

[2436] MS(EI): 419(M⁺).

[2437]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.19(3H,t,J=7.3 Hz), 1.61-1.63(2H,m), 1.90-1.94(2H,m), 2.84-2.88(3H,m), 4.02-4.07(4H,m), 5.40(1H,s), 7.26(1H,s), 7.41(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.80(1H,brs), 12.17(1H,brs).

Example 1029 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2438] The title compound was prepared from methanesulfonyl-chloride, ethyl isonipecotate 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2439] MP: 243° C.

[2440] MS(EI): 425(M⁺).

[2441]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.73-1.76(2H,m), 2.04-2.08 (2H,m), 2.74-2.78(3H,m), 2.88(3H,s), 3.66-3.69(2H,m), 5.41(1H,s), 7.27(1H,s), 7.42(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.93(1H,d,J=9.0 Hz), 9.84(1H,brs), 12.20(1H,brs).

Example 1030 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-(N,N-dimethylaminocarbonyl)piperidin-4-yl)-2H-pyrazolo[3,4-b]-pyridine

[2442] The title compound was prepared from 1-chloro-N,N-dimethylformamide, ethyl isonipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2443] MS(EI): 418(M⁺).

[2444]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.61-1.63(2H,m), 2.00-2.06 (2H,m), 2.65-2.67(2H,m), 2.75(6H,s), 2.81-2.85(1H,m), 3.64-3.67(2H,m), 5.40(1H,s), 7.27(1H,s), 7.41(1H,d,J=6.6 Hz), 7.59 (1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.86(1H,brs), 12.18(1H,brs).

Example 1031 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-guanylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2445] To a solution of 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.5 g) in MeOH (30 mL) was added diisopropylethylamine (4.2 g), and 1H-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (1.0 g) as yellow crystals.

[2446] MP: >270° C.

[2447] MS(EI): 389(M⁺).

[2448]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.53-1.56(2H,m), 1.86-1.91 (2H,m), 2.47-2.50(2H,m), 2.71-2.77(1H,m), 3.00-3.03(2H,m), 3.32-3.36(3H,br), 5.39(1H,s), 7.26(1H,s), 7.39(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.79(1H,brs), 12.21(1H,brs).

Example 1032 6-(1-Acetylpiperidin-3-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2449] The title compound was prepared from acetyl chloride, ethyl nipecotate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2450] MP: 219° C.

[2451] Anal. Calcd. For: C₂₀H₁₉N₇O₂:C,61.69;H,4.92;N,25.18.

[2452] Found: C,61.36;H,4.90;N,25.12.

[2453] MS(EI): 389(M⁺).

[2454]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.25-1.49(1H,m), 1.74-1.78 (2H,m), 2.00(3H,s), 2.01-2.04(1H,m), 2.49-2.98(3H,m), 3.78-3.81(1H,m), 4.37-4.40(1H,m), 5.29 and 5.42(1H,s), 7.28(1H,s), 7.41-7.48(1H,m), 7.58-7.62(1H,m), 7.92-7.95(1H,m), 9.90 (1H,brs), 12.21(1H,brs)

Example 1033 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-ethylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2455] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine and acetaldehyde in the same manner as in Example 1003.

[2456] MP: 231° C.

[2457] MS(EI): 375(M⁺).

[2458]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.99(3H,t,J=7.3 Hz), 1.60-1.63(2H,m), 1.85-1.88(2H,m), 2.00-2.04(2H,m), 2.31-2.34(2H,m), 2.64-2.66(1H,m), 2.97-3.00(2H,m), 5.39(1H,s), 7.26(1H,s), 7.40(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.75(1H,brs), 12.18(1H,brs).

Example 1034 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-propylpiperidin-4-yl)-2H-pyrazolo [3,4-b]pyridine

[2459] The title compound was prepared from 4-(2,1,3-Benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine and propionaldehyde in the same manner as in Example 1003.

[2460] MP: 246° C.

[2461] Anal. Calcd. For: C₂₁H₂₃N₇O:C, 64.76;H,5.95;N,25.18.

[2462] Found: C,64.23;H,5.87;N,24.86.

[2463] MS(EI): 389(M⁺).

[2464]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 1.40-1.45 (2H,m), 1.59-1.62(2H,m), 1.82-1.86(2H,m), 2.00-2.05(2H,m), 2.21(2H,t,J=7.3 Hz), 2.62-2.65(1H,m), 2.94-2.97(2H,m), 5.39 (1H,s), 7.26(1H,s), 7.40(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.91(1H,d,J=9.0 Hz), 9.77(1H,brs), 12.18(1H,brs).

Example 1035 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-iso-propylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2465] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine and acetone in the same manner as in Example 1003.

[2466] MP: 260° C.

[2467] MS(EI): 389(M⁺).

[2468]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.22(6H,d,J=7.3 Hz), 1.82-3.42 (10H,m), 5.40(1H,s), 7.27(1H,s), 7.42(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.66(1H,brs), 12.22(1H,brs).

Example 1036 4-(2-Bromo-3-cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2469] The title compound was prepared from ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2470] MP: >270° C.

[2471] Anal. Calcd. For: C₂₄H₂₅BrN₆O₂:C,56.59;H,4.95;N,16.50.

[2472] Found: C,56.47;H,4.87;N,16.52.

[2473] MS(EI): 509(M⁺).

[2474]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41(9H,s), 1.59-1.66(2H,m), 1.85-1.90(2H,m), 2.65-2.82(3H,m), 4.05-4.07(2H,m), 5.47(1H,s), 7.33(1H,s), 7.56-7.60(2H,m), 7.84(1H,d,J=7.3 Hz), 9.81(1H,brs), 12.26(1H,brs).

Example 1037 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2475] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2476] MP: >270° C.

[2477] MS(EI): 409(M⁺).

[2478]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.53-1.56(2H,m), 1.83-1.87(2H,m), 2.46-2.50(3H,m), 2.71-2.74(1H,m), 3.00-3.04(1H,m), 5.45(1H,s), 7.32(1H,s), 7.56-7.58(2H,m), 7.81(1H,d,J=7.3 Hz), 9.74(1H,brs), 12.26(1H,brs)

Example 1038 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2479] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo-[3,4-b]pyridine in the same manner as in Example 1003.

[2480] MP: >270° C.

[2481] MS(EI): 423(M⁺).

[2482]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.65-1.71(2H,m), 2.02-2.08 (3H,m), 2.29(3H,s), 2.48-2.52(1H,m), 1.66-1.69(1H,m), 2.95-2.98(2H,m), 5.50(1H,s), 7.34(1H,s), 7.55-7.57(2H,m), 7.83(1H,d,J=7.3 Hz), 9.83(1H,brs), 12.32(1H,brs).

Example 1039 4-(2-Bromo-3-cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2483] The title compound was prepared from ethyl nipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2484] MP: 238° C.

[2485] Anal. Calcd. For: C₂₄H₂₅BrN₆O₂:C, 56.56;H,4.95;N, 16.50.

[2486] Found: C,56.49;H,4.85;N,16.50.

[2487] MS(EI): 509(M⁺).

[2488]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.37 and 1.39(9H,s), 1.68-2.06(4H,m), 2.65-2.75(2H,m), 3.30-3.32(1H,m), 3.94-3.97 (2H,m), 5.47 and 5.49(1H,s), 7.34(1H,s), 7.58-7.61(2H,m), 7.82-7.86(1H,m), 9.89(1H,brs), 12.31(1H,brs).

Example 1040 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate

[2489] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-6-(1-t-butoxycarbonylpiperidin-3-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1021.

[2490] MP: 225° C.

[2491] Anal. Calcd. For: C₁₉H₁₇BrN₆CF₃COOH: C,48.20;H,3.47;N,16.06.

[2492] Found: C,47.98;H,3.52;N,15.97.

[2493] MS(EI): 409(M⁺).

[2494]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.68-1.98(4H,m), 2.65-2.68 (1H,m), 3.21-3.33(4H,m), 5.50(1H,s), 7.35(1H,s), 7.55-7.66 (2H,m), 7.84-7.87(1H,m), 8.54(1H,br), 8.96(1H,br), 9.96(1H,brs), 12.36(1H,br)

Example 1041 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2495] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-5-cyano-4,7-dihydro-6-(piperidin-3-yl)-2H-pyrazolo-[3,4-b]pyridine trifluoroacetate in the same manner as in Example 1003.

[2496] MP: 174° C.

[2497] MS(EI): 423(M⁺).

[2498]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.54-1.78(4H,m), 2.18-2.20 (1H,m), 2.20(3H,s), 2.55-2.58(2H,m), 2.94-2.96(1H,m), 3.31-3.34(1H,m), 5.47(1H,s), 7.33(1H,s), 7.57-7.58(2H,m), 7.84(1H,d,J=7.3 Hz), 10.06(1H,brs), 12.29(1H,brs).

Example 1042 4-(2-Bromo-3-cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2499] The title compound was prepared from ethyl pipecolinate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2500] MS(EI): 509(M⁺).

[2501]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.35(9H,s), 1.34-1.90(6H,m), 3.48-3.52(2H,m),,4.42-4.48(1H,m), 5.43 and 5.46(1H,s), 7.36-7.39(1H,m), 7.53-7.57(2H,m), 7.80-7.83(1H,m), 9.68 and 9.82(1H,brs), 12.26(1H,brs).

Example 1043 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-2-yl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate

[2502] The title compound was prepared from 4-(2-bromo-3-cyano-25 phenyl)-6-(1-t-butoxycarbonylpiperidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1021.

[2503] MP: 232° C.

[2504] MS(EI): 409(M⁺).

[2505]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.27-1.98(5H,m), 2.47-2.51 (2H,m), 3.12-3.18(1H,m), 4.7-4.10(1H,m), 4.50-4.57(1H,m), 7.40-7.63(3H,m), 7.79-7.82(2H,m), 8.06(1H,br), 10.93(1H,brs), 12.41(1H,brs).

Example 1044 4-(2-Bromo-3-cyanophenyl)-6-(4-t-butoxycarbonylmorpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2506] The title compound was prepared from ethyl morpholine-2-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazole in the same manner as in Example 1001.

[2507] MP: 219° C.

[2508] MS(EI): 511(M⁺).

[2509]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.40(9H,s), 2.97-3.10(2H,m), 3.47-3.53(1H,m), 3.77-3.94(3H,m), 4.37-4.39(1H,m), 5.52 and 5.54(1H,s), 7.34-7.36(1H,m), 7.58-7.65(2H,m), 7.94-7.96(1H,m), 9.87 and 9.92(1H,brs), 12.33(1H,brs).

Example 1045 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine trifluoroacetate

[2510] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-6-(4-t-butoxycarbonylmorpholin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1021.

[2511] MP: 236° C.

[2512] MS(EI): 411(M⁺).

[2513]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.02-3.05(1H,m), 3.24-3.33 (3H,m), 3.80-3.84(1H,m), 4.08-4.11(1H,m), 4.82-4.85(1H,m), 5.55(1H,s), 7.36(1H,s), 7.55-7.62(2H,m), 7.84-7.87(1H,m), 9.14(2H,br), 10.04-10.09(1H,brs), 12.40(1H,brs).

Example 1046 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[2514] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-5-cyano-4,7-dihydro-6-(morpholin-2-yl)-2H-pyrazolo-[3,4-b]pyridine trifluoroacetate in the same manner as in Example 1003.

[2515] MP: 180° C.

[2516] MS(EI): 425(M⁺).

[2517]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.18-2.20(1H,m), 2.20 and 2.21 (3H,s), 2.26-2.29(1H,m), 2.58-2.62(1H,m), 2.75-2.78(1H,m), 3.58-3.62(1H,m), 3.88-3.91(1H,m), 4.48-4.50(1H,m), 5.51(1H,s), 7.35(1H,s), 7.56-7.61(2H,m), 7.84-7.86(1H,m), 9.81 and 9.84(1H,brs), 12.31(1H,brs).

Example 1047 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2518] The title compound was prepared from ethyl 1,2,3,6-tetrahydropyridine-4-carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001, and Example 1002 followed.

[2519] MP: 226° C.

[2520] MS(EI): 407(M⁺).

[2521]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.36-2.40(2H,m), 2.95-2.98 (2H,m), 3.56-3.60(3H,m), 5.51(1H,s), 6.15(1H,s), 7.34(1H,s), 7.56-7.60(2H,m), 7.84(1H,d,J=7.3 Hz), 9.93(1H,brs), 12.32(1H,brs).

Example 1048 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2522] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-5-cyano-4,7-dihydro-6-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2523] MP: 233° C.

[2524] MS(EI): 421(M⁺).

[2525]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.31(3H,s), 2.56-2.67(4H,m), 3.00-3.03(2H,m), 5.50(1H,s), 6.10(1H,s), 7.34(1H,s), 7.58-7.60(2H,m), 7.83(1H,d,J=7.3 Hz), 9.91(1H,brs), 12.29(1H,brs).

Example 1049 4-(2-Bromo-3-cyanophenyl)-6-((N-t-butoxycarbonyl-N-methyl-amino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2526] The title compound was prepared from glycine ethyl ester hydrochloride, 2-bromo-3-cyanobenzaldehyde and 3-amino-pyrazole in the same manner as in Example 1015.

[2527] MS(EI): 469(M⁺).

[2528]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.39(9H,s), 2.85(3H,s), 4.15-4.18(2H,m), 5.49(1H,s), 7.37(1H,s), 7.56-7.57(2H,m), 7.83(1H,d,J=7.3 Hz), 9.78-9.93(1H,br), 12.31(1H,brs).

Example 1050 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-((N-methyl-amino)methyl)-2H-pyrazolo[3,4-b]pyridine trifluoracetate

[2529] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-6-((N-t-butoxycarbonyl-N-methylamino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1021.

[2530] MP: 258° C.

[2531] MS(EI): 369(M⁺).

[2532]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.10(3H,s), 4.46-4.66(2H,m), 5.50(1H,s), 7.47-7.48(2H,m), 7.65(1H,s), 7.80-7.81(2H,m), 8.09(1H,br), 10.81(1H,brs), 12.38(1H,brs).

Example 1051 6-(1-Acetylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2533] The title compound was prepared from acetyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2534] MP: >280° C.

[2535] MS(EI): 451(M⁺).

[2536]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.63-1.82(3H,m), 1.98-2.00 (1H,m), 2.00(3H,s), 2.49-2.51(1H,m), 2.94-3.10(2H,m), 3.89-3.91(1H,m), 4.48-4.50(1H,m), 5.47(1H,s), 7.34(1H,s), 7.56-7.58(2H,m), 7.84(1H,d,J=7.3 Hz), 9.81(1H,brs), 12.27(1H,brs).

Example 1052 6-(1-Benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2537] The title compound was prepared from benzoyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2538] MP: >280° C.

[2539] MS(FAB):514(M⁺+1).

[2540]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.64-2.04(4H,m), 2.76-2.80 (1H,m), 3.05-3.10(2H,m), 3.60-3.63(1H,m), 4.62-4.65(1H,m), 5.48(1H,s), 7.34-7.58(8H,m), 7.84(1H,d,J=7.3 Hz), 9.90(1H,brs), 12.31(1H,brs).

Example 1053 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2541] The title compound was prepared from methanesulfonyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2542] MP: >280° C.

[2543] MS(EI): 487(M⁺).

[2544]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.75-2.07(4H,m), 2.76-2.79 (2H,m), 2.89(3H,s), 3.66-3.69(2H,m), 5.48(1H,s), 7.34(1H,s), 7.56-7.58(2H,m), 7.84(1H,d,J=7.3 Hz), 9.84(1H,brs), 12.30(1H,brs).

Example 1054 6-(1-t-Butoxycarbonylpiperidin-4-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2545] The title compound was prepared from ethyl isonipecotate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2546] MP: >280° C.

[2547] Anal. Calcd. For: C₂₃H₂₆ClN₅O₂:C,62.79;H,5.96;N,15.92.

[2548] Found: C,62.81;H,5.87;N,16.01.

[2549] MS(EI): 439(M⁺).

[2550]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41(9H,s), 1.58-1.67(2H,m), 1.86-1.91(2H,m), 2.84-2.90(3H,m), 4.06-4.09(2H,m), 5.35(1H,s), 7.21-7.33(4H,m), 7.42(1H,d,J=7.3 Hz), 9.69(1H,brs), 12.18(1H,brs).

Example 1055 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2551] The title compound was prepared from 6-(1-t-butoxy-carbonylpiperidin-4-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2552] MP: 221° C.

[2553] MS(EI): 339(M⁺).

[2554]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.84-1.92(2H,m), 2.10-2.16 (2H,m), 2.96-3.00(3H,m), 3.30-3.40(2H,m), 5.36(1H,s), 7.22-7.33(4H,m), 7.42(1H,d,J=7.2 Hz), 8.56(1H,br), 9.76(1H,brs), 12.26(1H,brs).

Example 1056 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2555] The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]-pyridine trifluoroacetate in the same manner as in Example 1003.

[2556] MP: >270° C.

[2557] Anal. Calcd. For: C₁₉H₂₀ClN₅:C,64.49;H,5.70;N,19.79.

[2558] Found: C,64.71;H,5.68;N,19.59.

[2559] MS(EI): 353(M⁺).

[2560]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.56-1.65(2H,m), 1.84-1.90 (2H,m), 2.02-2.06(2H,m), 2.16(3H,s), 2.60-2.65(1H,m), 2.85-2.88(2H,m), 5.34(1H,s), 7.21-7.33(4H,m), 7.41(1H,d,J=7.3 Hz), 9.63(1H,brs), 12.17(1H,brs).

Example 1057 2-Acetyl-6-(1-acetylpiperidin-4-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2561] To a solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in pyridine (1.2 mL) was added acetic anhydride (0.42 mL) at room temperature and the mixture was stirred for two hours. The mixture was evaporated under reduced pressure and the residue was washed with methanol and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.

[2562] MS(EI): 423(M⁺).

[2563]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.58-1.70(2H,m), 1.91-1.96 (1H,m), 1.99-2.00(1H,m), 2.02(3H,s), 2.51(3H,s), 2.55-2.58 (1H,m), 3.11-3.18(2H,m), 3.91-3.94(1H,m), 4.49-4.52(1H,m), 5.37(1H,s), 7.32-7.37(3H,m), 7.48(1H,d,J=7.3 Hz), 7.84(1H,s), 10.24(1H,brs).

Example 1058 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine

[2564] To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at −78° C. Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.

[2565] To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in methanol (30 mL) was added 4N HCl dioxane solution (6.0 mL) at room temperature and the mixture was heated at 60° C. for two hours. After alkalification with sodium bicarbonate, the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (20 mg) as colorless crystals.

[2566] MP: >270° C.

[2567] MS(EI): 360(M⁺).

[2568]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.74-1.80(5H,m), 2.60-2.65(3H,m), 3.31-3.35(1H,m), 5.98(1H,s), 6.92(1H,d,J=6.6 Hz), 7.39(1H,s), 7.47(1H,dd,J=9.0 Hz and 6.6 Hz), 7.84(1H,d,J=9.0 Hz), 9.33(1H,brs), 12.15(1H,brs).

Example 1059 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine

[2569] The title compound was prepared from ethyl 4-cyclohexanonecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1058.

[2570] MS(FAB):361(M++l).

[2571]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.96-2.12(3H,m), 2.22-2.30(3H,m), 2.48-2.51(1H,m), 3.27-3.31(2H,m), 5.42(1H,s), 7.26(1H,s), 7.38-7.46(1H,m), 7.57-7.61(1H,m), 7.88-7.95(1H,m), 9.76(1H,brs), 12.16(1H,br).

Example 1060 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(2-oxocyclopentan-1-yl)-2H-pyrazolo[3,4-b]pyridine

[2572] The title compound was prepared from ethyl 2-cyclopentanonecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1058.

[2573] MS(FAB):347(M⁺+1).

[2574]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.60-1.63(2H,m), 1.86-2.05(2H,m), 2.31-2.34(2H,m), 3.43-3.46(1H,m), 5.47(1H,s), 7.25 and 7.30(1H,s), 7.39-7.46(1H,m), 7.56-7.60(1H,m), 7.91-7.94(1H,m), 9.90(1H,brs), 12.20(1H,brs)

Example 1061 6-Acetylmethyl-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2575] The title compound was prepared from ethyl acetoacetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1058.

[2576] MP: 200° C.

[2577] MS(FAB):321(M⁺+1).

[2578]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.22(3H,s), 3.63-3.66(2H,m), 5.48(1H,s), 7.30(1H,s), 7.47(1H,d,J=6.6 Hz), 7.61(1H,dd,J=9.0 Hz and 6.6 Hz), 7.94(1H,d,J=9.0 Hz), 10.00(1H,brs), 12.21(1H,brs).

Example 1062 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine

[2579] The title compound was prepared from ethyl 2-cyclohexanonecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1058.

[2580] MP: 273° C.

[2581] MS(EI): 422(M⁺).

[2582]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.72-1.81(5H,m), 2.59-2.65(3H,m), 3.30-3.32(1H,m), 5.91(1H,s), 7.05(1H,d,J=7.3 Hz), 7.40-7.43(2H,m), 7.52(1H,s), 7.74(1H,d,J=7.3 Hz), 9.33(1H,brs), 12.24(1H,brs).

Example 1063 6-Acetylmethyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2583] The title compound was prepared from ethyl acetoacetate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1058.

[2584] MP: 230° C.

[2585] MS(EI): 382(M⁺).

[2586]¹H-NMR (400 MHz,DMSO-d₆)8(ppm): 2.23(3H,s), 3.60-3.67(2H,m), 5.50(1H,s), 7.39(1H,s), 7.60(1H,dd,J=7.3 Hz and 7.2 Hz), 7.70(1H,d,J=7.3 Hz), 7.83(1H,d,J=7.3 Hz), 9.97(1H,brs), 12.29(1H,brs).

Example 1064 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride

[2587] 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(1-t-butoxy-carbonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (2.0 g) was added to 4N-HCl dioxane solution (20 mL) at 0° C. and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure and the residue was washed by ethanol, and the precipitated crystals were collected by filtration to give the title compound (1.2 g) as yellow crystals.

[2588] MS(EI): 339(M⁺).

[2589]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.83-1.90(2H,m), 2.07-2.15(2H,m), 2.94-2.97(3H,m), 3.34-3.37(2H,m), 5.36(1H,s), 7.22-7.33(4H,m), 7.42(1H,d,J=7.3 Hz), 8.41(1H,br), 9.17(1H,br), 9.77(1H,brs), 12.27(1H,brs).

Example 1065 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride

[2590] The title compound was prepared from 4-(2,1,3-benzoxa-diazol-4-yl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1064.

[2591] MP: >270° C.

[2592] Anal. Calcd. For: C₁₈H₁₇N₇OHCl: C,56.09;H,5.20;N,24.10.

[2593] Found: C,55.80;H,5.00;N,23.80.

[2594] MS(EI): 347(M⁺).

[2595]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.82-1.85(2H,m), 2.14-2.20(2H,m), 2.93-2.99(3H,m), 3.34-3.36(2H,m), 5.40(1H,s), 7.27(1H,s), 7.43(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 8.44(1H,br), 9.21(1H,br), 9.87(1H,brs), 12.25(1H,brs).

Example 1066 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2596] The title compound was prepared from 4-(2-bromo-3-cyanophenyl)-6-(1-t-butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1064.

[2597] MP: >270° C.

[2598] MS(EI): 409(M⁺).

[2599]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.84-1.92(2H,m), 2.07-2.10(2H,m), 2.92-2.98(5H,m), 5.48(1H,s), 7.34(1H,s), 7.57-7.59(2H,m), 7.84(1H,dd,J=7.3 Hz and 7.2 Hz), 8.30(1H,br), 9.04(1H,br), 9.90(1H,brs), 12.35(1H,br).

Example 1067 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2600] The title compound was prepared from ethyl 1-t-butoxy-carbonylpyrrolidine-2-carboxylate, 2-bromo-3-cyano-benzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2601] MS(EI): 495(M⁺).

[2602]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.47(9H,s), 1.82-1.97(4H,m), 2.31(1H,m), 3.50(1H,m), 4.53(1H,m), 5.47(1H,s), 7.51-7.91 (4H,m), 9.83(1H,m), 12.26(1H,s).

Example 1068 4-(2-Bromo-3-cyanophenyl)-5-cyano-6-(pyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2603] The title compound was prepared from 4-(2-bromo-3-cyano-phenyl)-5-cyano-6-(1-t-butoxycarbonylpyrrolidin-2-yl)-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2604] MP: >240° C.

[2605] MS(EI): 395(M⁺).

[2606]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.39-1.55(1H,m), 1.97(2H,m), 2.30(1H,m), 3.32(2H,m), 4.10-4.28(1H,m), 5.41(1H,s), 6.52(1H,s), 7.34-7.47(2H,m), 7.70(1H,dd,J=8.3 Hz and 9.0 Hz), 11.89(1H,brs).

Example 1069 4-(2,1,3-Benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpyrrolidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2607] The title compound was prepared from ethyl 1-t-butoxycarbonylpyrrolidine-2-carboxylate, 2,1,3-benzoxadiazole-4-aldehyde and ³-aminopyrazole in the same manner as in Example 1001.

[2608] MS(EI): 433(M⁺).

[2609]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.40(9H,s), 1.78-1.89(4H,m), 2.11-2.31(1H,m), 3.72(1H,m), 4.53(1H,m), 5.40(1H,s), 7.26(1H,s), 7.30-7.40(1H,m), 7.58(1H,dd,J=6.4 Hz and 9.6 Hz), 7.91(1H,d,J=9.6 Hz), 9.86(1H,s), 12.16(1H,s).

Example 1070 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(pyrrolidin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[2610] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-6-(1-t-butoxycarbonylpyrrolidin-2-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2611] MP: >240° C.

[2612] MS(EI): 333(M⁺).

[2613]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41-1.46(1H,m), 1.97-2.14(4H,m), 3.72(1H,m), 4.11-4.32(1H,m), 5.52(1H,s), 7.00(1H,s), 7.26(1H,s), 7.30-7.42(1H,m), 7.58(1H,dd,J=6.4 Hz and 9.6 Hz), 7.91(1H,d,J=9.3 Hz), 11.87(1H,s).

Example 1071 6-(¹-t-Butoxycarbonylpyrrolidin-2-yl)-4-(2-chlorophenyl)-5-cyano-4,⁷-dihydro-2H-pyrazolo[3,4-b]pyridine

[2614] The title compound was prepared from ethyl 1-t-butoxy-carbonylpyrrolidine-2-carboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2615] MS(EI): 425(M⁺).

[2616]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.36(9H,s), 1.86(4H,m), 2.32(1H,m), 3.54(1H,m), 4.57(1H,m), 5.38(1H,s), 7.23-7.27(4H,m), 7.42(1H,d,J=7.6 Hz), 9.68(1H,s), 12.17(1H,s).

Example 1072 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-2H-pyrazolo[3,4-b]pyridine

[2617] The title compound was prepared from ethyl 1-t-butoxy-carbonylpiperidine-4-carboxylate, 2,3-(methylenedioxy)-benzaldehyde and ³-aminopyrazole in the same manner as in Example 1001.

[2618] MS(EI): 449(M⁺).

[2619]¹H-NMR (400 MHz,DMSO-d₆)8(ppm): 1.39(1H,m), 1.97-2.13(2H,m), 2.00(2H,m), 2.78-3.15(2H,m), 3.31(1H,m), 3.96(2H,s), 5.03(1H,d,J=9.5 Hz), 6.00-6.02(1H,m), 6.64(1H,d,J=2.9 Hz), 6.78(1H,d,J=1.7 Hz), 7.29(1H,s), 9.46(1H,s), 12.18(1H,s).

Example 1073 5-Cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2620] The title compound was prepared from 6-(1-t-butoxy-carbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-2H-pyrazolo[3,4-b]-pyridine in the same manner as in Example 1002.

[2621] MS(EI): 390(M⁺).

[2622]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.27-1.88(5H,m), 2.49-2.96(5H,m), 5.02(1H,s), 6.00-6.02(2H,m), 6.66(1H,m), 6.76(2H,m), 7.27(1H,s), 9.98(1H,s), 12.14(1H,s).

Example 1074 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine-6-carboxylic acid phenylamide

[2623] The title compound was prepared from N-phenyloxamic acid ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2624] MS(EI): 375(M⁺).

[2625]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.50(1H,s), 7.13(1H,dd,J=7.1 Hz and 7.6 Hz), 7.25-7.46(7H,m), 7.66(2H,dd,J=8.3 Hz), 10.4(1H,s), 10.76(1H,s), 12.3(1H,s).

Example 1075 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-6-carboxylic acid phenylamide

[2626] The title compound was prepared from N-phenyloxamic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2627] MS(EI): 383(M⁺).

[2628]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 5.59(1H,s), 7.11-7.15 (1H,dd,J=7.3 Hz and 7.6 Hz), 7.33-7.36(3H,m), 7.51(1H,d,J=6.6 Hz), 7.63-7.68(3H,m), 7.96(1H,d,J=9.0 Hz), 10.52(1H,s), 10.76(1H,s), 12.3(1H,s).

Example 1076 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-[4-(naphthalen-1-yl)piperazin-1-yl]methyl-2H-pyrazolo[3,4-b]pyridine trihydrochloride

[2629] 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyl-oxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (20 g) in tetrahydrofuran (200 mL) was added a THF solution (49.9 mL) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (800 mL), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) and carbon tetrabromide (15.4 g) in methylene chloride (340 mL) was added triphenylphosphine (12.2 g) in methylene chloride (100 mL) under ice-cooling and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (3.84 g) as a pale-yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mL) was added 1-(naphthalen-1-yl)piperazine (334 mg) and the mixture was stirred under ice-cooling for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (500 mg) under ice-cooling and the mixture was stirred under ice-cooling for 6 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (1:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals.

[2630] MP: 203-205° C (decomposition)

[2631] MS(EI): 481(M⁺).

[2632]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.31-3.70(8H,m), 4.33(2H,m), 4.85(3H,m), 5.54(1H,s), 7.19(1H,d,J=7.3 Hz), 7.29-7.54(8H,m), 7.67(1H,d,J=8.1 Hz), 7.92(1H,d,J=7.1 Hz), 8.15(1H,d,J=7.3 Hz), 10.35(1H,s), 11.28(1H,brs).

Example 1077 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(4-methyl-homopiperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine dihydrochloride

[2633] The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and N-methylhomopiperazine in the same manner as in Example 1076.

[2634] MP: 204-206° C. (decomposition)

[2635] MS(EI): 382(M⁺).

[2636]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.22(2H,m), 2.78(3H,s), 3.24-4.11(12H,m), 5.48(1H,s), 7.14-7.35(4H,m), 7.45(1H,d,J=8.0 Hz), 10.17(1H,brs), 11.51(1H,brs).

Example 1078 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(4-phenylpiperazin-l-yl)methyl-2H-pyrazolo[3,4-b]pyridine trihydrochloride

[2637] The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and 1-phenylpiperazine in the same manner as in Example 1076.

[2638] MP: 217-220° C. (decomposition)

[2639] MS(EI): 430(M⁺).

[2640]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 3.20-4.00(9H,m), 4.27(2H,m), 5.51(1H,s), 6.86(1H,t,J=7.1 Hz), 7.01(2H,d,J=8.0 Hz), 7.24-7.39(6H,m), 7.45(1H,d,J=9.9 Hz), 9.50(1H,brs), 10.37(1H,s), 11.40(1H,brs).

Example 1079 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-phthalimidomethyl-2H-pyrazolo[3,4-b]pyridine

[2641] To a solution of 4-(?-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.8 g) in DMF (10 mL) was added potassium phthalimide (445 mg) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-hexane (2:1)) to give the title compound (285 mg) as white crystals.

[2642] MP: >250° C.

[2643] MS(EI): 416(M⁺).

[2644]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 4.66(2H,d,J=2.4 Hz), 5.40(1H,s), 7.24-7.45(5H,m), 7.82-7.94(4H,m), 10.04(1H,s), 12.23(1H,s).

Example 1080 6-Acetyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2645] 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(1,1-dimethoxyethyl)-2H-pyrazolo[3,4-b]pyridine was prepared from methyl 2,2-dimethoxypropionate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001. To a solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(1,1-dimethoxyethyl)-2H-pyrazolo[3,4-b]pyridine (1.0 g) in dichloromethane (10 mL) was added a trifluoroacetic acid (10 mL) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (370 mg) as white crystals.

[2646] MP: 225-228° C. (decomposition)

[2647] MS(EI): 298(M⁺).

[2648]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.56(3H,s), 5.49(1H,s), 7.25-7.36(4H,m), 7.45(1H,d,J=7.8 Hz), 10.12(1H,s), 12.50(1H,brs).

Example 1081 6-Acetyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2649] The title compound was prepared from 2-bromo-3-cyano-benzaldehyde, 3-aminopyrazole and methyl 2,2-dimethoxy-propionate in the same manner as in Example 1001.

[2650] MP: >230° C.

[2651] MS(EI): 368(M⁺).

[2652]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.42(3H,s), 5.54(1H,s), 7.32(1H,brs), 7.50-7.59(2H,m), 7.80(1H,dd,J=1.7 Hz and 7.3 Hz), 10.19(1H,s), 12.39(1H,brs).

Example 1082 6-Acetyl-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2653] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and methyl 2,2-dimethoxypropionate in the same manner as in Example 1001.

[2654] MP: 230° C. (decomposition)

[2655] MS(EI): 306(M⁺).

[2656]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.55(3H,s), 5.54(1H,s), 7.33(1H,s), 7.49(1H,d,J=6.6 Hz), 7.61(1H,dd,J=6.6 Hz and 8.6 Hz), 7.96(1H,d,J=9.2 Hz), 10.27(1H,s), 12.36(1H,brs).

Example 1083 6-(1-Benzyl-2-oxopyrrolidin-4-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2657] The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl 1-benzyl-2-oxopyrrolidine-4-carboxylate in the same manner as in Example 1001.

[2658] MP: >230° C.

[2659] Anal. Calcd. for: C₂₄H₂₀ClN₅O:C,67.05;H,4.69;N,16.29.

[2660] Found: C,66.86;H,4.56;N,16.31.

[2661] MS(EI): 429(M⁺).

[2662]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.60(1H,dd,J=9.5 Hz and 16.4 Hz), 2.81(1H,dd,J=10.5 Hz and 16.4 Hz), 3.39(1H,m), 3.47(1H,m), 4.42(2H,m), 5.36(1H,s), 7.23-7.43(10H,m), 10.04(1H,s), 12.21(1H,s).

Example 1084 4-(2-Bromo-3-cyanophenyl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2663] To a solution of 2-picoline (10 g) in THF (75 mL) was added n-BuLi (113 mmol) at −40° C. Further, methyl butanoate (15.8 mL) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 2-(2-oxopentanyl)pyridine (4.8 g) as a yellow oil. A solution of 2-bromo-3-cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2-(2-oxopentanyl)pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 mL) was heated under reflux for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the obtained crystals (520 mg) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (3.4 g) solution was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give oil. The obtained oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to give a yellow solid (530 mg). To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred with heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give oil. To the obtained oil was added water and the mixture was extracted with ethyl acetate. The extract was washed a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as a pale-yellow crystal.

[2664] MP: 205-208° C. (decomposition)

[2665] Anal. Calcd. for: C₂₁H₁₈BrN₅:C,60.01;H,4.32;N,16.66.

[2666] Found: C,59.83;H,4.42;N,16.26 .

[2667] MS(EI): 420(M⁺).

[2668]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.83(3H,t,J=7.6 Hz), 1.62(2H,m), 2.24(1H,m), 2.33(1H,m), 5.93(1H,s), 6.98(1H,dd,J=4.9 Hz and 7.3 Hz), 7.05(1H,d,J=7.8 Hz), 7.28(1H,m), 7.39(1H,m), 7.51-7.60(3H,m), 8.36(1H,d,J=3.6 Hz), 8.52(1H,s), 11.84(1H,s).

Example 1085 6-(1-tert-Butoxycarbonylpyrrolidin-3-yl)-4-(2-chlorophenyl)-5-cyano-4,,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2669] To a solution of methyl 1-benzyl-2-oxopyrrolidine-4-carboxylate (10.9 g) in THF (50 mL) was added 1.0 M borane in THF (84 mL) under ice-cooling and the mixture was refluxed for 1 hour. Decomposition of excess borane and boron complexes was effected by the dropwise addition of 30 mL of methanolic hydrogen chloride followed by refluxing for 1 hour. After removal of the solvents under reduced pressure another 30 mL of methanolic hydrogen chloride was added, and the mixture was refluxed an additional 1 hour. The solvents were again removed in vacuo and the residue was treated with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 g) as a pale yellow oil. A suspension of methyl 1-benzyl-3-pyrrolidinecarboxylate (4.8 mg), 5% palladium on carbon (300 mg) and ammonium formate (2.8 g) in methanol (50 mL)-water (5 mL) was refluxed for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol (9:1)) to give methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) was added dimethylaminopyridine (161 mg) and di-tert-butyldicarbonate (3.4 g) at 0° C. and the mixture was stirred for 13 hours. The mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) to give methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added n-BuLi (12.4 mmol) at −78° C. Further, methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) to give 1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-2-cyanoethan-1-one (2.35 g) as a colorless oil. A solution of 2-chlorophenylaldehyde (1.4 g), 3-aminopyrazole (819 mg) and 1-(1-tert-butoxy-carbonylpyrrolidin-3-yl)-2-cyanoethan-1-one (2.35 g) in acetonitrile (10 mL) was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.18 g) as colorless crystals.

[2670] Anal. Calcd. For: C₂₂H₂₄ClN₅O₂:C, 62.04;H,5.68;N,16.44.

[2671] Found: C,61.94;H,5.69;N,16.45.

[2672] MS(EI): 425(M⁺).

[2673]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.14(9H,s), 2.07(1H,m), 2.32(1H,m), 3.29-3.58(5H,m), 5.37(1H,s), 7.22-7.34(4H,m), 7.42(1H,d,J=8.3 Hz), 9.78(1H,s), 12.20(1H,s).

Example 1086 4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(pyrrolidin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2674] 6-(1-tert-Butoxycarbonylpyrrolidin-3-yl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (706 mg) was added to 4N-HCl dioxane solution (5 mL) at room temperature and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue was washed by ethanol-ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (460 mg) as colorless crystals.

[2675] MP: 210-215° C. (decomposition)

[2676] MS(EI): 325(M⁺).

[2677]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 2.24(2H,m), 3.15(1H,m), 3.26-3.55(3H,m), 3.64(1H,m), 5.34(1H,s), 5.40(1H,brs), 7.23-7.32(4H,m), 7.43(1H,d,J=7.3 Hz), 9.38(1H,brs), 9.51(1H,brs), 9.97(1H,s).

Example 1087 4-(2,1,3-Benzoxadiazol-4-yl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2678] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, Meldrum's acid, 2-(2-oxopentanyl)pyridine and ammonium acetate in the same manner as in Example 1084.

[2679] MS(EI): 358(M⁺).

[2680]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 1.64(2H,m), 2.27(1H,m), 2.35(1H,m), 5.96(1H,s), 6.95(1H,m), 7.11-7.18(3H,m), 7.40(1H,m), 7.51(1H,m), 7.69(1H,d,J=9.3 Hz), 8.35(1H,m), 8.54(1H,s), 11.78(1H,brs).

Example 1088 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(indan-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2681] The title compound was prepared from ethyl isonipecotate, 4-indancarboxaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2682] MS(EI): 445(M⁺).

[2683]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm) 1.41(9H,s), 1.56-1.59(2H,m), 1.88-1.06(4H,m), 2.58-2.83(7H,m), 4.06(2H,m), 4.96(1H,s), 6.90(1H,m), 7.04-7.07(2H,m), 7.14(1H,s), 9.55(1H,s), 12.08(1H,s)

Example 1089 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(2,3-dihydrobenzo[b]furan-7-yl)-2H-pyrazolo[3,4-b]pyridine

[2684] The title compound was prepared from ethyl isonipecotate, 7-(2,3-dihydrobenzo[b]furan)carboxaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2685] MS(EI): 445(M⁺).

[2686]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.42(9H,s), 1.57-1.66(2H,m), 1.88(4H,m), 2.73-2.90(3H,m), 3.17(2H,m), 4.09(2H,m), 4.54(2H,m), 5.01(1H,s), 6.76(1H,m), 6.84(1H,d,J=7.1 Hz), 7.05(1H,d,J=6.6 Hz), 7.22(1H,s), 9.52(1H,s), 12.0⁶(1H,s).

Example 1090 6-(1-t-Butoxycarbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(3, 4-dihydro-2H-benzopyran-8-yl)-2H-pyrazolo [3,4-b]pyridine

[2687] The title compound was prepared from ethyl isonipecotate, 8-(3,4-dihydro-2H-benzopyrane)carboxaldehyde and 3-amino-pyrazole in the same manner as in Example 1001.

[2688] MS(EI): 461(M⁺).

[2689]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.42(9H,s), 1.58-1.69(2H,m), 1.80-2.00(4H,m), 2.73-2.95(5H,m), 4.09(2H,m), 4.22(2H,m), 5.14(1H,s), 6.74(1H,m), 6.84-6.89(2H,m), 7.21(1H,s), 9.48(1H,s), 12.03(1H,s).

Example 1091 6-(1-t-Butoxycarbonylpiperidin-4-yl)-4-(2-chloro-3-trifluoromethylphenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine

[2690] The title compound was prepared from ethyl isonipecotate, 2-15 chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2691] MS(EI): 461(M⁺).

[2692]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.41(9H,s), 1.62(2H,m), 1.89 (2H,m), 2.60-2.90(3H,m), 4.10(2H,m), 5.54(1H,s), 7.32(1H,s), 7.52-7.56(2H,m), 7.75(1H,d,J=9.3 Hz), 9.79(1H,s), 12.25(1H,s).

Example 1092 5-Cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2693] The title compound was prepared from 6-(1-t-butoxy-25 carbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2694] MS(EI): 361(M⁺).

[2695]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.83-1.98(4H,m), 2.14(2H,m), 2.74(2H,m), 2.90-3.00(3H,m), 4.22(2H,m), 3.40-3.70(5H,m), 4.16-4.27(2H,m), 5.15(1H,s), 6.74(1H,m), 6.83-6.89(2H,m), 7.22(1H,s), 9.54(1H,s)

Example 1093 5-Cyano-4,7-dihydro-4-(indan-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2696] The title compound was prepared from 6-(1-t-butoxy-carbonylpiperidin-4-yl)-5-cyano-4,7-dihydro-4-(indan-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1002.

[2697] MS(EI): 345(M⁺).

[2698]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.80-1.99(4H,m), 2.14(2H,m), 2.58(1H,m), 2.82-2.95(6H,m),3.30-3.50(2H,m), 4.97(1H,s), 6.90(1H,m), 7.04-7.09(2H,m), 7.17(1H,s), 8.37(1H,m), 9.10(1H,m), 9.62(1H,s), 12.18(1H,brs).

Example 1094 5-Cyano-4,7-dihydro-4-(indan-4-yl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2699] The title compound was prepared from 5-cyano-4,7-dihydro-4-(indan-4-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2700]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.56(2H,m), 1.84-1.98(6H,m), 2.15(2H,m), 2.58(1H,m), 2.80-3.00(6H,m), 3.20-3.40(2H,m), 4.95(1H,s), 6.90(1H,m), 7.05-7.07(2H,m), 7.14(1H,s), 9.54(1H,brs), 12.10(1H,brs).

Example 1095 5-Cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2701] The title compound was prepared from 5-cyano-4,7-dihydro-4-(3,4-dihydro-2H-benzopyran-8-yl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2702]¹H-NMR (400 MHz,DMSO-d₆)δ(ppm): 1.90-2.00(4H,m), 2.24(2H,m), 2.73-2.75(5H,m), 2.94-3.08(3H,m), 3.40-3.48(2H,m), 4.17-4.27(2H,m), 5.15(1H,s), 6.74(1H,m), 6.84-6.89(2H,m), 7.22(1H,s), 9.58(1H,s), 9.80(1H,m), 12.15(1H,s).

Example 1096 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-2-yl)-2H-pyrazolo[3,4-b]pyridine

[2703] The title compound was prepared from methanesulfonyl-chloride, ethyl pipecolinate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1025.

[2704] MS(EI): 425(M⁺).

[2705]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.20-2.07(7H,m), 2.95 and 2.98(3H,s), 2.98-3.17(1H,m), 3.63-3.68(1H,m), 5.40 and 5.52(1H,s), 7.24 and 7.27(1H,s), 7.41-7.63(2H,m), 7.90-7.93(1H,m), 9.80 and 9.82(1H,brs), 12.16(1H,brs).

Example 1097 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2706] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1064.

[2707] MS(EI): 361(M⁺).

[2708]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.86-1.90(2H,m), 2.24-2.27(2H,m), 2.48(3H,s), 2.72-2.75(2H,m), 2.94-2.98(2H,m), 3.20-3.33(1H,br), 3.44-3.47(1H,m), 5.40(1H,s), 7.28(1H,s), 7.44(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.93(1H,d,J=9.0 Hz), 9.92(1H,brs), 12.26(1H,brs).

Example 1098 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2709] The title compound was prepared from 1,2-dihydro-1-methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2710] MS(EI): 371(M⁺).

[2711]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 3.46(3H,s), 5.42(1H,s), 6.34(1H,d,J=7.2 Hz), 6.56(1H,s), 7.33(1H,s), 7.52(1H,d,J=7.2 Hz), 7.61(1H,dd,J=9.0 Hz and 6.6 Hz), 7.80(1H,d,J=6.6 Hz), 7.95(1H,d,J=9.0 Hz), 10.33(1H,brs), 12.29(1H,brs).

Example 1099 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,2,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2712] The title compound was prepared from 1,2,3,4-tetrahydropyridine-3-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2713] MS(EI): 345(M⁺).

[2714]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.42-2.44(2H,m), 3.11-3.14(2H,m) 3.84-3.87(2H,m), 4.39(1H,br), 5.46(1H,s), 6.36(1H,s), 7.30(1H,s), 7.49(1H,d,J=6.6 Hz), 7.56(1H,dd,J=9.0 Hz and 6.6 Hz), 7.94(1H,d,J=9.0 Hz), 9.39(2H,br), 10.06(1H,brs).

Example 1100 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2715] The title compound was prepared from 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4,5,6-tetrahydropyridin-3-yl)-20 2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2716] MS(EI): 359(M⁺).

[2717]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.18-2.20(2H,m), 2.43-2.47(2H,m) 3.02-3.11(2H,m), 5.43(1H,s), 6.11(1H,s), 7.26(1H,s), 7.43(1H,d,J=6.6 Hz), 7.59(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.87(1H,brs), 12.16(1H,brs).

Example 1101 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-(methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2718] The title compound was prepared from 2-methylglycine ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1015 and 1002.

[2719] MS(EI): 321(M⁺).

[2720]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.56(3H,d,J=6.8 Hz), 3.07(3H,s), 4.59-4.68(3H,m), 5.66(1H,s), 7.29(1H,d,J=6.6 Hz), 7.44(1H,s), 7.52(1H,dd,J=9.0 Hz and 6.6 Hz), 7.87(1H,d,J=9.0 Hz), 8.22(1H,br), 8.44(1H,br), 10.95(1H,brs).

Example 1102 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2721] The title compound was prepared from 1,2-dihydro-1-methyl-2-oxo-pyridine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2722] MS(EI): 433(M⁺).

[2723]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 3.46(3H,s), 5.35(1H,s), 6.37(1H,d,J=7.2 Hz), 6.61(1H,s), 7.38(1H,s), 7.60(1H,dd,J=7.3 Hz and 7.2 Hz), 7.72-7.86(3H,m), 10.31(1H,brs), 12.37(1H,brs).

Example 1103 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-(methylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2724] The title compound was prepared from 4-aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1015 and 1002.

[2725] MS(EI): 436(M⁺).

[2726]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.39(2H,m), 1.80-1.90(4H,m), 2.15-2.16(2H,m), 2.84-2.86(1H,m), 3.14-3.16(1H,m), 4.20(2H,br) 5.46(1H,s), 7.33(1H,s), 7.56-7.57(2H,m), 7.82(1H,d,J=7.3 Hz), 8.98(2H,br), 9.80(1H,brs).

Example 1104 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,2,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride

[2727] The title compound was prepared from 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2728] MS(EI): 407(M⁺).

[2729]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.43-2.44(2H,m), 3.13-3.15(2H,m) 3.70-3.72(2H,br), 3.86-3.88(2H,m), 5.54(1H,s), 6.41(1H,s) 7.36(1H,s), 7.58(1H,dd,J=7.3 Hz and 7.2 Hz), 7.84(1H,d,J=7.3 Hz), 7.86(1H,d,J=7.3 Hz), 9.32(2H,br), 10.03(1H,brs).

Example 1105 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-(dimethylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine

[2730] The title compound was prepared from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-(methylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003 .

[2731] MS(EI): 450(M⁺).

[2732]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.26-1.29(2H,m), 1.76-1.93(6H,m) 2.27(6H,s), 2.34-2.36(1H,m), 2.63-2.66(1H,m), 5.45(1H,s) 7.33(1H,s), 7.56-7.60(2H,m), 7.82(1H,d,J=7.3 Hz), 9.74(1H,brs), 12.27(1H,s).

Example 1106 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2733] The title compound was prepared from 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1,4,5,6-tetrahydropyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2734] MS (E I): 420(M⁺).

[2735]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 2.21-2.22(2H,m), 2.28(3H,s), 2.48-2.49(2H,m), 3.08-3.12(2H,m), 5.49(1H,s), 6.15(1H,s), 7.33(1H,s), 7.56-7.61(2H,m), 7.84(1H,dd,J=7.3 Hz and 7.2 Hz), 9.87(1H,brs), 12.26(1H,brs).

Example 1107 6-(exo-2-Azabicyclo[2,2,2]octan-6-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2736] The title compound was prepared from exo-2-azabicyclo[2,2,2]octane-6-carboxylic acid. ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2737] MS(EI): 373(M⁺).

[2738]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.53-1.55(1H,m), 1.75-1.77(1H,m) 1.89-2.06(4H,m), 2.21-2.23(1H,m), 3.07-3.10(2H,m), 3.43-3.48(4H,m), 5.39-5.43(1H,s), 7.26-7.28(1H,m), 7.44-7.47(1H,m), 7.57-7.61(1H,m), 7.93-7.95(1H,m), 8.87-9.03(1H,br) 9.46-9.52(1H,br), 9.73 and 9.80(1H,brs).

Example 1108 6-(endo-2-Azabicyclo[2,2,2]octan-6-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2739] The title compound was prepared from endo-2-azabicyclo[2,2,2]octane-6-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2740] MS(EI): 373(M⁺).

[2741]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.67-1.73(3H,m), 2.03-2.13(4H,m) 3.04-3.06(1H,m), 3.34-3.57(5H,m), 5.49(1H,s), 7.30(1H,s) 7.50-7.51(1H,m), 7.58-7.60(1H,m), 7.92-7.94(1H,m), 8.07(1H,br), 9.79(1H,br), 9.89(1H,br).

Example 1109 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(exo-2-methyl-2-azabicyclo[2,2,2]octan-6-yl)-2H-pyrazolo[3,4-b]pyridine

[2742] The title compound was prepared from 6-(exo-2-azabicyclo[2,2,2]octan-6-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2743] MS(EI): 387(M⁺).

[2744]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.43-1.44(1H,m), 1.70-1.90(5H,m) 2.11-2.13(1H,m), 2.38-2.46(4H,m), 3.00-3.02(1H,m), 3..32-3.36(2H,m), 5.38 and 5.40(1H,s), 7.25-7.27(1H,m), 7.38-7.42(1H,m), 7.56-7.61(1H,m), 7.90-7.93(1H,m), 9.73(1H,br) 12.23(1H,br).

Example 1110 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 Hydrobromide

[2745] A solution of 2,1,3-benzoxadiazole-4-aldehyde (3.0 g), Meldrum's acid (3.0 g), ethyl 3-keto-3-(1-benzylcarbonylpiperidin-4-yl)propionate (6.8 g) and ammonium acetate (1.8 g) in acetic acid (20 mL) was stirred under reflux for 12 hrs. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (4.7 g). To a solution of dimethylformamide (2.7 g) in chloroform (10 mL) were added phosphorus oxychloride (3.4 mL) and a solution of the obtained colorless crystals (4.7 g) in chloroform (10 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (37.8 g) solution was added and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.4 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (840 mg) as colorless crystals. To a solution of the obtained colorless crystals in acetic acid (10 mL) was added HBr-AcOH solution (10 mL) and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure to give colorless crystals. The crystal was purified by recrystalization from EtOH to give the title compound (630 mg) as colorless crystals.

[2746] MS(EI): 394(M⁺).

[2747]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.77(3H,t,J=7.3 Hz), 1.80-2.16(4H,m), 2.90-2.93(2H,m), 3.40-3.43(2H,m), 3.80(2H,q,J=7.3 Hz), 4.12-4.15(1H,m), 4.50(2H,br), 5.67(1H,s), 7.17(1H,d,J=6.6 Hz), 7.26(1H,s), 7.51(1H,dd,J=9.0 Hz and 6.6 Hz), 7.79(1H,d,J=9.0 Hz), 8.10(1H,br), 8.74(1H,br), 9.38(1H,brs).

Example 1111 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(endo-2-methyl-2-azabicyclo[2,2,2]octan-6-yl)-2H-pyrazolo[3,4-b]pyridine

[2748] The title compound was prepared from 6-(endo-2-azabicyclo[2,2,2]octan-6-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2749] MS(EI): 387(M⁺).

[2750]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.43-1.47(2H,m), 1.60-1.64(2H,m) 1.81-1.82(1H,m), 1.79-2.06(2H,m), 2.24-2.26(1H,m), 2.36(3H,s), 2.76-2.80(2H,m), 3.19-3.22(1H,m), 5.43(1H,s), 7.25(1H,s), 7.42-7.46(1H,m), 7.57-7.60(1H,m), 7.90-7.94(1H,m) 10.79(1H,brs), 12.16(1H,brs).

Example 1112 Ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 Hydrochloride

[2751] The title compound was prepared from ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate in the same manner as in Example 1003.

[2752] MS(EI): 408(M⁺).

[2753]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.75(3H,t,J=7.3 Hz), 1.55-1.56(1H,m), 1.71-1.73(1H,m), 1.87-2.06(4H,m), 2.17(3H,s), 2.84-2.87(2H,m), 3.78(2H,q,J=7.3 Hz), 3.93-3.96(1H,m), 5.68(1H,s), 7.12(1H,d,J=6.6 Hz), 7.22(1H,s), 7.49(1H,dd,J=9.0 Hz and 6.6 Hz), 7.77(1H,d,J=9.0 Hz), 9.32(1H,brs), 12.06(1H,brs).

Example 1113 4-(2-Bromophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2754] The title compound was prepared from ethyl nipecotate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2755] MS(EI): 383(M⁺).

[2756]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.85-1.93(2H,m), 2.14-2.20(2H,m) 2.94-2.98(2H,m), 3.32-3.36(3H,m), 5.36(1H,s), 7.16(1H,dd,J=7.3 Hz and 7.2 Hz), 7.23-7.27(2H,m), 7.35(1H,dd,J=7.3 Hz and 7.2 Hz), 7.59(1H,d,J=7.3 Hz), 8.41(1H,br), 9.14(1H,br), 9.73(1H,brs), 12.21(1H,brs).

Example 1114 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(piperidin-4-yl)-2¹H-pyrazolo[3,4-b]pyridine Hydrochloride

[2757] The title compound was prepared from ethyl nipecotate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2758] MS(EI): 335(M⁺).

[2759]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.87-1.95(2H,m), 2.14-2.20(2H,m) 2.94-3.03(3H,m), 3.32-3.36(2H,m), 3.82(3H,s), 5.21(1H,s), 6.88(1H,dd,J=7.3 Hz and 7.2 Hz), 6.99(1H,d,J=7.3 Hz), 7.05(1H,d,J=7.3 Hz), 7.15-7.20(2H,m), 8.44(1H,br), 9.17(1H,br) 9.53(1H,brs), 12.11(1H,brs).

Example 1115 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2760] The title compound was prepared from ethyl nipecotate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2761] MS(EI): 373(M⁺).

[2762]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.84-1.90(2H,m), 2.16-2.20(2H,m) 2.94-3.00(3H,m), 3.32-3.38(2H,m), 5.44(1H,s), 7.24-7.36(3H,m), 7.56(1H,d,J=7.3 Hz), 8.52(1H,br), 9.24(1H,br), 9.79(1H,brs), 12.29(1H,brs).

Example 1116 4-(2-Bromophenyl)-5-cyano-4,-7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2763] The title compound was prepared from 4-(2-bromophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003 .

[2764] MS(EI): 397(M⁺).

[2765]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.56-1.63(2H,m), 1.85-1.90(2H,m) 2.01-2.06(2H,m), 2.17(3H,s), 2.62-2.65(1H,m), 2.87-2.89(2H,m), 5.34(1H,s), 7.14-7.26(3H,m), 7.36(1H,dd,J=7.3 Hz and 7.2 Hz), 7.60(1H,d,J=7.3 Hz), 9.60(1H,brs), 12.16(1H,brs)

Example 1117 5-Cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2766] The title compound was prepared from 5-cyano-4,7-dihydro-4-(2-methoxyphenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine in the same manner as in Example 1003.

[2767] MS(EI): 349(M⁺).

[2768]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.56-1.66(2H,m), 1.86-1.92(2H,m) 2.01-2.04(2H,m), 2.17(3H,s), 2.64-2.67(1H,m), 2.86-2.88(2H,m), 3.84(3H,s), 5.20(1H,s), 6.90(1H,dd,J=7.3 Hz and 7.2 Hz), 6.98(1H,d,J=7.3 Hz), 7.05(1H,d,J=7.3 Hz), 7.16-7.19(2H,m), 9.41(1H,brs), 12.01(1H,brs).

Example 1118 5-Cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2769] The title compound was prepared from 5-cyano-4-(2,3-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2770] MS(EI): 387(M⁺).

[2771]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.57-1.65(2H,m), 1.85-1.90(2H,m) 2.01-2.06(2H,m), 2.17(3H,s), 2.59-2.66(1H,m), 2.86-2.89(2H,m), 5.43(1H,s), 7.23(1H,d,J=7.3 Hz), 7.29(1H,s), 7.35(1H,dd,J=7.3 Hz and 7.2 Hz), 7.51(1H,d,J=7.3 Hz), 9.65(1H,brs) 12.18(1H,brs).

Example 1119 5-Cyano-4,7-dihydro-4-(2-fluorophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2772] The title compound was prepared from ethyl nipecotate, 2-fluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2773] MS(EI): 323(M⁺).

[2774]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.85-1.89(2H,m), 2.12-2.20(2H,m) 2.90-2.98(3H,m), 3.33-3.39(2H,m), 5.20(1H,s), 7.14-7.28(5H,m), 8.37(1H,br), 9.09(1H,br), 9.66(1H,brs), 12.23(1H,brs).

Example 1120 5-Cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2775] The title compound was prepared from ethyl nipecotate, 2,3-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2776] MS(EI): 341(M⁺).

[2777]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.84-1.88(2H,m), 2.14-2.19(2H,m) 2.95-3.00(3H,m), 3.33-3.38(2H,m), 5.26(1H,s), 7.03(1H,d,J=7.3 Hz), 7.18(1H,dd,J=7.3 Hz and 7.2 Hz), 7.26-7.31(2H,m), 8.80(2H,br), 9.74(1H,brs), 12.29(1H,brs).

Example 1121 5-Cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2778] The title compound was prepared from ethyl nipecotate, 2,6-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2779] MS(EI): 341(M⁺).

[2780]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.76-1.84(2H,m), 2.13-2.18(2H,m) 2.91-2.95(3H,m), 3.28-3.30(2H,m), 5.35(1H,s), 7.02-7.07(2H,m), 7.31.-7.38(2H,m), 8.77(2H,br), 9.68(1H,brs), 12.22(1H,brs).

Example 1122 5-Cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2781] The title compound was prepared from ethyl nipecotate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2782] MS(EI): 351(M⁺).

[2783]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.86-1.93(2H,m), 2.17-2.23(2H,m) 2.50(3H,s), 2.95-3.00(3H,m), 3.36-3.40(4H,m), 5.36(1H,s) 7.14-7.33(5H,m), 8.49(1H,br), 9.22(1H,br), 9.63(1H,brs).

Example 1123 5-Cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2784] The title compound was prepared from ethyl nipecotate, 2,6-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2785] MS(EI): 373(M⁺).

[2786]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.80-1.84(2H,m), 2.12-2.20(2H,m) 2.90-2.98(3H,m), 3.30-3.33(2H,m), 5.92(1H,s), 7.19(1H,s) 7.29(1H,dd,J=7.3 Hz and 7.2 Hz), 7.38(1H,d,J=7.3 Hz), 7.51(1H,d,J=7.3 Hz), 8.41(1H,br), 9.16(1H,br), 9.73(1H,brs) 12.18(1H,brs).

Example 1124 5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2787] The title compound was prepared from ethyl nipecotate, 2-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2788] MS(EI): 373(M⁺)

[2789]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.83-1.90(2H,m), 2.18-2.26(2H,m) 2.92-3.00(3H,m), 3.38-3.43(2H,m), 4.16(2H,br), 5.22(1H,s) 7.06(1H,s), 7.42-7.44(2H,m), 7.63-7.69(2H,m), 8.57(1H,br) 9.30(1H,br), 9.77(1H,br).

Example 1125 5-Cyano-4,7-dihydro-4-(2-fluorophenyl)-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2790] The title compound was prepared from 5-cyano-4,7-dihydro-4-(2-fluorophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2791] MS(EI): 337(M⁺).

[2792]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.55-1.59(2H,m), 1.83-1.88(2H,m), 1.96-2.00(2H,m), 2.15(3H,s), 2.60-2.63(1H,m), 2.84-2.88(2H,m), 5.17(1H,s), 7.13-7.24(5H,m), 9.60(1H,brs), 12.18(1H,brs).

Example 1126 5-Cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2793] The title compound was prepared from 5-cyano-4-(2,3-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2794] MS(EI): 355(M⁺).

[2795]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.55-1.59(2H,m), 1.82-1.8(2H,m), 1.99-2.02(2H,m), 2.15(3H,s), 2.57-2.60(1H,m), 2.84-2.88(2H,m), 5.23(1H,s), 7.00(1H,dd,J=7.3 Hz and 7.2 Hz), 7.16(1H,d,J=7.3 Hz), 7.27-7.30(2H,m), 9.66(1H,brs), 12.24(1H,brs).

Example 1127 5-Cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2796] The title compound was prepared from 5-cyano-4-(2,6-difluorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2797] MS(EI): 355(M⁺).

[2798]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.49-1.53(2H,m), 1.82-1.86(2H,m), 1.96-2.01(2H,m), 2.15(3H,s), 2.48-2.51(1H,m), 2.83-2.86(2H,m), 5.31(1H,s), 7.00-7.05(2H,m), 7.29-7.31(2H,m), 9.60(1H,brs), 12.15(1H,brs).

Example 1128 5-Cyano-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2799] The title compound was prepared from ethyl nipecotate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in

Examples 1001 and 1002.

[2800] MS(EI): 351(M⁺).

[2801]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.84-1.93(2H,m), 2.17-2.23(2H,m), 2.94-3.00(3H,m), 3.35-3.38(2H,m), 4.42(2H,br), 5.40(1H,s), 7.30(1H,s), 7.46-7.51(2H,m), 7.71(1H,dd,J=7.3 Hz and 7.2 Hz), 7.90(1H,d,J=7.3 Hz), 8.61(1H,br), 9.36(1H,br), 9.87(1H,brs).

Example 1129 5-Cyano-4,7-dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2802] The title compound was prepared from ethyl nipecotate, benzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2803] MS(EI): 305(M⁺).

[2804]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.81-1.89(2H,m), 2.14-2.20(2H,m), 2.90-2.96(3H,m), 3.32-3.35(2H,m), 4.20(2H,br), 4.89(1H,s), 7.17-7.22(4H,m), 7.28-7.31(2H,m), 8.58(1H,br), 9.32(1H,br), 9.65(1H,brs).

Example 1130

[2805] 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(2-methylthiophenyl)-2H-pyrazolo[3,4-b]pyridine

[2806] The title compound was prepared from 5-cyano-4,7-dihydro-4-(2-methylthiophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2807] MS(EI): 366(M⁺)

[2808]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.58-1.66(2H,m), 1.83-1.89(2H,m), 1.97-2.02(2H,m), 2.15(3H,s), 2.50(3H,s), 2.62-2.65(1H,m), 2.84-2.87(2H,m), 5.32(1H,s), 7.12-7.30(5H,m), 9.57(1H,brs), 12.18(1H,brs).

Example 1131 5-Cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2809] The title compound was prepared from 5-cyano-4-(2,6-dichlorophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine hydrochloride in the same manner as in Example 1003.

[2810] MS(EI): 387(M⁺)

[2811]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.52-1.56(2H,m), 1.83-1.87(2H,m), 1.99-2.06(2H,m), 2.15(3H,s), 2.52-2.55(1H,s), 2.83-2.87(2H,m), 5.90(1H,s), 7.17(1H,s), 7.28(1H,dd,J=7.3 Hz and 7.2 Hz), 7.36(1H,d,J=7.3 Hz), 7.48(1H,d,J=7.3 Hz), 9.67(1H,brs), 12.12(1H,brs).

Example 1132 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine

[2812] The title compound was prepared from 5-cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(2-trifluoromethylphenyl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2813] MS(EI): 387(M⁺).

[2814]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.57-1.62(2H,m), 1.83-1.86(2H,m), 1.97-2.03(2H,m), 2.16(3H,s), 2.60-2.63(1H,m), 2.84-2.87(2H,m), 5.18(1H,s), 7.05(1H,s), 7.40-7.42(2H,m), 7.62-7.68(2H,m), 9.69(1H,brs), 12.23(1H,brs).

Example 1133 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(2-nitrophenyl)-2H-pyrazolo[3,4-b]pyridine

[2815] The title compound was prepared from 5-cyano-4,7-dihydro-4-(2-nitrophenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2816] MS(EI): 365(M⁺)

[2817]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.58-1.67(2H,m), 1.86-1.90(2H,m), 1.99-2.06(2H,m), 2.16(3H,s), 2.58-2.61(1H,m), 2.86-2.90(2H,m), 5.36(1H,s), 7.26(1H,s), 7.42-7.48(2H,m), 7.69(1H,dd,J=7.3 Hz and 7.2 Hz), 7.88(1H,d,J=7.3 Hz), 9.72(1H,brs), 12.26(1H,brs).

Example 1134 5-Cyano-4,7-dihydro-4-phenyl-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2818] The title compound was prepared from 5-cyano-4,7-dihydro-4-phenyl-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2819] MS(EI): 319(M⁺).

[2820]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.54-1.57(2H,m), 1.81-1.87(2H,m), 1.97-2.03(2H,m), 2.15(3H,s), 2.58-2.60(1H,m), 2.84-2.86(2H,m), 4.87(1H,s), 7.17-7.20(4H,m), 7.27-7.32(2H,m), 9.52(1H,brs), 12.13(1H,brs).

Example 1135 5-Cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2821] The title compound was prepared from ethyl butanoate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2822] MS(EI): 322(M⁺).

[2823]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.93(3H,t,J=7.3 Hz), 1.63-1.68(2H,m), 2.34-2.45(2H,m), 5.16(1H,s), 7.02(1H,d,J=7.3 Hz), 7.18(1H,dd,J=7.3 Hz and 7.2 Hz), 7.28(1H,d,J=7.2 Hz), 9.88(1H,brs), 12.22(1H,brs).

Example 1136 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2824] The title compound was prepared from ethyl nipecotate, 2,1,3-benzothiadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2825] MS(EI): 363(M⁺).

[2826]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.89-1.98(2H,m), 2.22-2.29(2H,m), 2.98-3.05(3H,m), 3.37-3.43(2H,m), 5.20(2H,br), 5.72(1H,s), 7.24(1H,s), 7.48(1H,d,J=6.6 Hz), 7.72(1H,dd,J=9.0 Hz and 6.6 Hz), 7.99(1H,d,J=9.0 Hz), 8.68(1H,br), 9.43(1H,br), 9.86(1H,brs).

Example 1137 5-Cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2827] The title compound was prepared from ethyl nipecotate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2828] MS(EI): 385(M⁺).

[2829]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.82-1.85(2H,m), 2.16-2.22(2H,m), 2.95-3.00(3H,m), 3.34-3.39(2H,m), 5.17(1H,s), 5.65(2H,br), 7.05(1H,d,J=7.3 Hz), 7.19(1H,dd,J=7.3 Hz and 7.2 Hz), 7.29(1H,d,J=7.3 Hz), 7.33(1H,s), 8.65(1H,br), 9.43(1H,br), 9.86(1H,brs).

Example 1138 4-(2,1,3-Benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2830] The title compound was prepared from 4-(2,1,3-benzothiadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2831] MS(EI): 377(M⁺)

[2832]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.64-1.73(2H,m), 1.91-1.97(2H,m), 2.05-2.09(2H,m), 2.419(3H,s), 2.70-2.72(1H,m), 2.90-2.93(2H,m), 5.71(1H,s), 7.22(1H,s), 7.45(1H,d,J=6.6 Hz), 7.72(1H,dd,J=9.0 Hz and 6.6 Hz), 7.98(1H,d,J=9.0 Hz), 9.71(1H,brs), 12.13(1H,brs).

Example 1139 5-cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2833] The title compound was prepared from 5-cyano-4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2834] MS(EI): 399(M⁺).

[2835]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.5-1.58(2H,m), 1.86-1.90(2H,m), 1.99-2.03(2H,m), 2.16(3H,s), 2.59-2.62(1H,m), 2.85-2.89 (2H,m), 5.15(1H,s), 7.03(1H,d,J=7.3 Hz), 7.17(1H,dd,J=7.3 Hz and 7.2 Hz), 7.26-7.31(2H,m), 9.71(1H,brs), 12.26(1H,brs).

Example 1140 5-Cyano-4-(2-cyanophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride

[2836] The title compound was prepared from ethyl nipecotate, 2-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2837] MS(EI): 330(M⁺).

[2838]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.86-1.90(2H,m), 2.18-2.22(2H,m), 2.92-2.98(3H,m), 3.34-3.37(2H ,m), 5.10(2H,br), 5.25(1H,s), 7.27(1H,s), 7.43-7.47(2H,m), 7.68(1H,dd,J=7.3 Hz and 7.2 Hz), 7.82(1H,d,J=7.3 Hz), 8.61(1H,br), 9.41(1H,br), 9. 93(1H,brs).

Example 1141 5-Cyano-4-(2-cyanophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2839] The title compound was prepared from 5-cyano-4-(2-cyanophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2840] MS(EI): 344(M⁺)

[2841]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.58-1.63(2H,m), 1.82-1.87(2H,m), 1.98-2.06(2H,m), 2.16(3H,s), 2.59-2.61(1H,m), 2.84-2.88(2H,m), 5.23(1H,s), 7.25(1H,s), 7.39-7.46(2H,m), 7.6(1H,dd,J=7.3 Hz and 7.2 Hz), 7.81(1H,d,J=7.3 Hz), 9.77(1H,brs), 12.26(1H,brs).

Example 1142 5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine 3 Hydrochloride

[2842] The title compound was prepared from ethyl nipecotate, pyridine-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2843] MS(EI): 306(M⁺).

[2844]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.86-1.92(2H,m), 2.18-2.25(2H,m), 2.93-3.00(3H,m), 3.35-3.38(2H,m), 5.41(1H,s), 6.50(3H,br), 7.42(1H,s), 7.97(2H,d,J=6.8 Hz), 8.90(1H,br), 8.93(2H,d,J=6.8 Hz), 9.60(1H,br), 10.10(1H,brs).

Example 1143 5-Cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine 3 Hydrochloride

[2845] The title compound was prepared from ethyl nipecotate, pyridine-3-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2846] MS(EI): 306(M⁺)

[2847]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.86-1.93(2H,m), 2.19-2.25(2H,m), 2.90-2.97(3H,m), 3.35-3.38(2H,m), 5.39(1H,s), 6.50(3H,br), 7.41(1H,s), 8.09(1H,dd,J=8.2 Hz and 5.4 Hz), 8.49(1H,d,J=8.2 Hz), 8.72(1H,br), 8.88(1H,d,J=5.4 Hz), 8.92(1H,s), 9.57(1H,br), 10.02(1H,brs).

Example 1144 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2848] The title compound was prepared from 5-cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridine 3 hydrochloride in the same manner as in Example 1003.

[2849] MS(EI): 320(M⁺).

[2850]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.56-1.64(2H,m), 1.86-1.90(2H,m), 1.99-2.03(2H,m), 2.17(3H,s), 2.61-2.64(1H,m), 2.86-2.89(2H,m), 4.96(1H,s), 7.23(2H,d,J=6.8 Hz), 7.31(1H,s), 8.50(2H,d,J=6.8 Hz), 9.67(1H,brs), 12.25(1H,brs).

Example 1145 5-Cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine

[2851] The title compound was prepared from 5-cyano-4,7-dihydro-6-(piperidin-4-yl)-4-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine 3 hydrochloride in the same manner as in Example 1003.

[2852] MS(EI): 320(M⁺).

[2853]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.57-1.60(2H,m), 1.84-1.89(2H,m), 1.99-2.05(2H,m), 2.17(3H,s), 2.58-2.61(1H,m), 2.85-2.8(2H,m), 4.98(1H,s), 7.29(1H,s), 7.35(1H,dd,J=8.2 Hz and 5.4 Hz), 7.55(1H,d,J=8.2 Hz), 8.42-8.45(2H,m), 9.64(1H,brs), 12.23(1H,brs).

Example 1146 6-(exo-2-Azabicyclo[2,2,2]octan-6-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2854] The title compound was prepared from exo-2-azabicyclo[2,2,2]octane-6-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2855] MS(EI): 435(M⁺).

[2856]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.52-1.54(1H,m), 1.74-2.18(6H,m), 3.06-3.09(2H,m), 3.50-3.52(2H,m), 3.87(2H,br), 5.51(1H,s), 7.33(1H,d,J=7.3 Hz), 7.55-7.60(2H,m), 7.84(1H,d,J=7.3 Hz), 8.97(1H,br), 9.73(1H,br), 9.78(1H,brs).

Example 1147 6-(endo-2-Azabicyclo[2,2,2]octan-6-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2857] The title compound was prepared from endo-2-azabicyclo[2,2,2]octane-6-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.

[2858] MS(EI): 435(M⁺)

[2859]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.67-1.69(3H,m), 2.02-2.12(4H,m) 3.02-3.05(1H,m), 3.31-3.35(1H,m), 3.45-3.51(2H,m), 4.04(2H,br), 5.50(1H,s), 7.34(1H,s), 7.56(1H,dd,J=7.3 Hz and 7.2 Hz), 7.82(1H,d,J=7.3 Hz), 8.16(1H,br), 9.82(1H,br), 9.93(1H,brs).

Example 1148 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(exo-2-methyl-2-azabicyclo[2,2,2]octan-6-yl)-2H-pyrazolo[3,4-b]pyridine

[2860] The title compound was prepared from 6-(exo-2-azabicyclo[2,2,2]octan-6-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine 2 hydrochloride in the same manner as in Example 1003.

[2861] MS(EI): 449(M⁺).

[2862]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.42-1.45(1H,m), 1.72-1.88(5H,m) 2.06-2.09(1H,m), 2.46-2.51(4H,m), 3.04-3.07(1H,m), 3.45-3.48(2H,m), 5.48(1H,s), 7.34(1H,s), 7.57-7.60(2H,m), 7.83(1H,dd,J=7.3 Hz and 7.2 Hz), 9.83(1H,brs), 12.37(1H,brs).

Example 1149 Ethyl 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2863] A solution of 2,2-difluoro-1,3-benzodioxol-4-aldehyde (2.0 g), Meldrum's acid (1.6 g), ethyl 3-keto-hexanoate (1.7 g) and ammonium acetate (0.91 g) in acetic acid (20 mL) were stirred under reflux for 12 hrs. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (2.4 g). To a solution of dimethylformamide (1.9 g) in chloroform (10 mL) were added phosphorus oxychloride (4.0 g) and a solution of the obtained colorless crystals (2.4 g) in chloroforom (10 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (27 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.0 g), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (190 mg) as colorless crystals.

[2864] MS(EI): 391(M⁺).

[2865]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.90-0.97(6H,m), 1.58-1.64(2H,m) 2.60-2.64(1H,m), 2.83-2.86(1H,m), 3.83(2H,q,J=7.3 Hz), 5.32(1H,m), 6.86(1H,d,J=7.3 Hz), 7.03-7.11(2H,m), 7.24(1H,s) 9.61(1H,brs), 12.06(1H,brs).

Example 1150 Ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 Hydrobromide

[2866] The title compound was prepared from 2-bromo-3-cyanobenzaldehyde in the same manner as in Example 1110.

[2867] MS(EI): 455(M⁺)

[2868]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.84(3H,t,J=7.3 Hz), 1.78-1.81(1H,m), 1.98-2.14(3H,m), 2.87-2.90(2H,m), 3.40-3.42(2H,m) 3.78(2H,q,J=7.3 Hz), 3.80-4.25(3H,m), 5.64(1H,s), 7.35(1H,s), 7.40-7.47(2H,m), 7.70(1H,d,J=7.3 Hz), 8.10(1H,br) 8.73(1H,br), 9.37(1H,brs).

Example 1151 Ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate

[2869] The title compound was prepared from ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 hydrobromide in the same manner as in Example 1003.

[2870] MS(EI): 469(M⁺)

[2871]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.85(3H,t,J=7.3 Hz), 1.53-1.55(1H,m), 1.70-1.72(1H,m), 1.87-2.06(4H,m), 2.16(3H,s), 2.84-2.88(2H,m), 3.78(2H,q,J=7.3 Hz), 3.94-3.96(1H,m), 5.63(1H,s), 7.34-7.48(3H,m), 7.68(1H,d,J=7.3 Hz), 9.34(1H,brs) 12.16(1H,brs).

Example 1152 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-2-oxo-piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2872] The title compound was prepared from 1-methyl-2-oxo-piperidine-4-carboxylic acid ethyl ester, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2873] MS(EI): 375(M⁺).

[2874]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.88-1.91(1H,m), 2.26-2.33(2H,m) 2.65-2.70(1H,m), 2.82(3H,m), 3.17-3.20(1H,m), 3.31-3.36(2H,m), 5.40(1H,s), 7.29(1H,s), 7.44(1H,d,J=6.6 Hz), 7.58(1H,dd,J=9.0 Hz and 6.6 Hz), 7.92(1H,d,J=9.0 Hz), 9.88(1H,brs) 12.22(1H,brs).

Example 1153 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-2-oxo-piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine

[2875] The title compound was prepared from 1-methyl-2-oxo-piperidine-4-carboxylic acid ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001.

[2876] MS(EI): 437(M⁺)

[2877]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.88-1.92(1H,m), 2.25-2.36(2H,m) 2.69-2.74(1H,m), 2.84(3H,s), 3.18-3.36(3H,m), 5.50(1H,s) 7.37(1H,s), 7.59-7.62(2H,m), 7.85(1H,d,J=7.3 Hz), 9.90(1H,brs), 12.33(1H,brs).

Example 1154 4-(2-Chlorophenyl)-4,7-dihydro-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2878] A solution of 2-chlorobenzaldehyde (21 g), Meldrum's acid (21 g), 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (16 g). A 1N NaOH solution (100 mL) was added, and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was acidified. The reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give colorless crystals (9.6 g). Hydrazine (0.22 g) and CDI (0.66 g) were added to the obtained colorless crystals (1.0 g) in DMF (5 mL), and the mixture was stirred for 3 hours. And the precipitated crystals were collected by filtration to give colorless crystals (0.7 g). Orthoacetic acid triethyl ester (3.7 g) was added to the obtained colorless crystals (1.0 g) in DMF (5 mL), and the mixture was heated for 3 hours. And the precipitated crystals were collected by filtration to give colorless crystals (0.6 g). To a solution of dimethylformamide (0.55 g) in chloroform (3 mL) were added phosphorus oxychloride (1.2 g) and a solution of the obtained colorless crystals in chloroform (6 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (7.7 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (10 mL) was added hydrazine (0.15 g), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (170 mg) as colorless crystals.

[2879] MS(EI): 356(M⁺).

[2880]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.00(3H,t,J=7.3 Hz), 1.67-1.74(2H,m), 2.31(3H,s), 2.70-2.83(2H,m), 5.71(1H,s), 7.07-7.12(3H,m), 7.33-7.40(2H,m), 9.49(1H,brs), 12.04(1H,brs).

Example 1155 4-(2-Bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-(methylamino)ethyl)-2H-pyrazolo[3,4-b]pyridine 2 Hydrochloride

[2881] The title compound was prepared from 2-methylglycine ethyl ester, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1015 and 1002.

[2882] MS(EI): 384(M⁺)

[2883]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.49(3H,d,J=7.3 Hz), 3.09(3H,s) 4.00(2H,br), 4.60(1H,q,J=7.3 Hz), 5.53(1H,s), 7.48-7.53(2H,m), 7.64(1H,s), 7.82(1H,d,J=7.3 Hz), 8.00-8.29(2H, r), 10.97(1H,brs).

Example 1156 4-(2-Chlorophenyl)-4,7-dihydro-5-(5-methyl-1,2,4-oxadiazol-3-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2884] A solution of 2-chlorobenzaldehyde (21 g), Meldrum's acid (21 g), 3-keto-hexanoic acid 2-cyanoethyl ester (27 g) and ammonium acetate (13 g) in acetic acid (150 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (16 g). A 1N NaOH solution (100 mL) was added, and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was acidified. The reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give colorless crystals (9.6 g). An Ammonia solution (3.0 g) and CDI (2.8 g) were added to the obtained colorless crystals (4.2 g) in DMF (20 mL), and the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give an oil. The residue in N,N-dimethylacetamide dimethyl acetal (30 mL) solution was heated for 2 hours, and the solvent was evaporated under reduced pressure. Hydroxyammonium (1.4 g), 1N NaOH (20 mL), dioxane (20 mL) and acetic acid (28 mL) were added to the residue, and the mixture was heated for one hour. The reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the colorless crystals (1.3 g). To a solution of dimethylformamide (1.7 g) in chloroform (10 mL) were added phosphorus oxychloride (3.5 g) and a solution of the obtained colorless crystals in chloroforom (20 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (23 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (15 mL) was added hydrazine (0.6 g), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (500 mg) as colorless crystals.

[2885] MS(EI): 356(M⁺).

[2886]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 0.99(3H,s), 1.62(3H,t,J=7.3 Hz), 1.66-1.73(2H,m), 2.13(3H,s), 2.35-2.38(2H,m), 2.84-3.05(2H,m), 5.73(1H,s), 7.06-7.17(3H,m), 9.90(1H,brs), 12.11(1H,brs).

Example 1157 4-(2,1,3-Benzoxadiazol-4-yl)-4,7-dihydro-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2887] The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde in the same manner as in Example 1154.

[2888] MS(EI): 364(M⁺)

[2889]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.01(3H,t,J=7.3 Hz), 1.69-1.76(2H,m), 2.31(3H,s), 2.72-2.86(2H,m), 5.82(1H,s), 7.18(1H,d,J=6.6 Hz), 7.32(1H,s), 7.48(1H,dd,J=9.0 Hz and 6.6 Hz), 7.80(1H,d,J=9.0 Hz), 9.65(1H,brs), 12.07(1H,brs).

Example 1158 4-(2-Bromo-3-cyanophenyl)-4,7-dihydro-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine

[2890] The title compound was prepared from 2-bromo-3-cyanobenzaldehyde in the same manner as in Example 1154.

[2891] MS(EI): 425(M⁺)

[2892]¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 1.00(3H,t,J=7.3 Hz), 1.66-1.73(2H,m), 2.33(3H,s)., 2.74-2.78(2H,m), 5.78(1H,s), 7.40-7.47(3H,m), 7.69(1H,dd,J=7.3 Hz and 7.2 Hz), 9.63(1H,brs), 12.14(1H,brs).

Example 1159 6-(1-Amino-1-methylethyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine Hydrochloride

[2893] The title compound was prepared from 2,2-dimethylglycine ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1015 and 1002.

Formulation Example 1

[2894] The compound of Example 1 (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were thoroughly mixed and kneaded well with a binder made of corn starch (2 parts). The kneaded product was passed through a 16 mesh sieve, dried in an oven at 50° C. and passed through a 24 mesh sieve. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were thoroughly mixed and compression-punched to give tablets containing 0.5 mg of the active ingredient per tablet.

Formulation Example 2

[2895] The compound of Example 1 (1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, and the solution was filtered to remove pyrogen. The filtrate was transferred into an ampoule under sterile conditions. After sterilization, the ampoule was weld-sealed to give injection containing 1.0 mg of the active ingredient.

[2896] The effects of the compounds of the present invention on glycogen synthase kinase-3 beta (GSK-3β) were evaluated and confirmed as follows.

Formulation Example 3

[2897] The compound of Example 1001 (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were thoroughly mixed and kneaded well with a binder made of corn starch (2 parts). The kneaded product was passed through a 16 mesh sieve, dried in an oven at 50° C. and passed through a 24 mesh sieve. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were thoroughly mixed and compression-punched to give tablets containing 0.5 mg of the active ingredient per tablet.

Formulation Example 4

[2898] The compound of Example 1001(1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, and the solution was filtered to remove pyrogen. The filtrate was transferred into an ampoule under sterile conditions. After sterilization, the ampoule was weld-sealed to give injection containing 1.0 mg of the active ingredient.

[2899] The effects of the compounds of the present invention on glycogen synthase kinase-3 beta (GSK-3β) were evaluated and confirmed as follows.

Experimental Example 1 GSK-3β-inhibitory Activity

[2900] CREB phosphopeptide (4.6 mmol), rabbit GSK-3β (0.5 unit), ATP (5 mmol), [γ-³²P]ATP (12.3 kBq) and a test compound were reacted in a GSK-3β buffer solution (25 μL) (20 mmol/L Tris-HCl (pH 7.5), 10 mmol/L magnesium chloride, 5 mmol/L dithiothreitol) containing 1% dimethyl sulfoxide, at 30° C. for 20 minutes. The reaction product (10 μL) was adsorbed on a P81 ion-exchange paper, and the paper was washed with phosphoric acid (100 mmol/L) and measured for cpm on a scintillation counter. As a result, the compounds of the present invention showed the IC₅₀ values of 1 to 1000 mmol/L. For example, the IC₅₀ values of the compounds of Examples 1, 14, 27, 66 and 140 were 210, 170, 25, 51 and 24 mmol/L, respectively.

[2901] CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser-Arg-Arg-Pro-Ser(P)-Tyr-Arg.

Experimental Example 2 GSK-3β-inhibitory Activity in Rat Cultured Hippocampal Neurons

[2902] Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor), and the culture was continued for 3 hours, whereby phosphorylation of Tau protein was induced. After the completion of culture, the level of phosphorylation of Tau protein was determined by EIA method using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β), and the inhibitory effect of the GSK-3β inhibitor on the neurons was evaluated. FIG. 1 shows the GSK-3β-inhibitory activity of the compounds of Example 47 and Example 137.

Experimental Example 3 Effect on Amyloid β-induced Cytotoxicity in Rat Cultured Hippocampal Neurons

[2903] Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor), and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined and the effect of the GSK-3β inhibitor on the amyloid β-induced cytotoxicity was evaluated. FIG. 2 shows the effect of the compounds of Example 66 on amyloid β-induced cytotoxicity.

Experimental Example 4 GSK-3β-inhibitory Effect in Gerbil Brain Ischemia Model

[2904] A test compound (GSK-3β inhibitor) was intraperitoneally administered to gerbils and 30 minutes later, brain ischemia was created by shutting off (for 4 minutes) all carotid arteries, whereby phosphorylation of Tau protein in the brain was induced. Three hours after the brain ischemia, the hippocampus was obtained from the gerbil brain and the level of phosphorylation of Tau protein was determined by Western blot using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β), based on which the GSK-3β-inhibitory effect of the GSK-3β inhibitor in the gerbil brain was evaluated. FIG. 3 shows the GSK-3β-inhibitory effect of the compounds of Example 27 in gerbil brain ischemia model.

Experimental Example 5 GSK-3β-inhibitory Activity

[2905] CREB phosphopeptide (4.6 mmol), rabbit GSK-3β (0.5 unit), ATP (5 mmol), [γ-³²P]ATP (12.3 kBq) and a test compound were reacted in a GSK-3β buffer solution (25 μL) (20 mmol/L Tris-HCl (pH 7.5), 10 mmol/L magnesium chloride, 5 mmol/L dithiothreitol) containing 1% dimethyl sulfoxide, at 30° C. for 20 minutes. The reaction product (10 μL) was adsorbed on a P81 ion-exchange paper, and the paper was washed with phosphoric acid (100 mmol/L) and measured for cpm on a scintillation counter. As a result, the compounds of the present invention showed the IC₅₀ values of 1 to 1000 mmol/L. For example, the IC₅₀ values of the compounds are shown in the following Table 1.

[2906] CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser-Arg-Arg-Pro-Ser(P)-Tyr-Arg. TABLE 1 Example No. IC₅₀ (nmol/L) 1002 10 1003 2.5 1008 3.7 1011 14 1023 4.1 1058 1.8 1063 3.0 1146 0.61 1148 3.2 1155 2.2 1158 0.65

Experimental Example 6 GSK-3β-inhibitory Activity in Rat Cultured Hippocampal Neurons

[2907] Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor), and the culture was continued for 3 hours, whereby phosphorylation of Tau protein was induced. After the completion of culture, the level of phosphorylation of Tau protein was determined by EIA method using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β), and the inhibitory effect of the GSK-3β inhibitor on the neurons was evaluated.

Experimental Example 7 Effect on Amyloid β-induced Cytotoxicity in Rat Cultured Hippocampal Neurons

[2908] Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor), and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined, and the effect of the GSK-3β inhibitor on the amyloid β-induced cytotoxicity was evaluated.

Experimental Example 8 GSK-3β-inhibitory Effect in Gerbil Brain Ischemia Model

[2909] A test compound (GSK-3β inhibitor) was intraperitoneally administered to gerbils, and 30 minutes later, brain ischemia was created by shutting off (for 4 minutes) all carotid arteries, whereby phosphorylation of Tau protein in the brain was induced. Three hours after the brain ischemia, the hippocampus was obtained from the gerbil brain, and the level of phosphorylation of Tau protein was determined by Western blot using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β), based on which the GSK-3β-inhibitory effect of the GSK-3β inhibitor in the gerbil brain was evaluated.

[2910] The compounds of the present invention show a selective and strong inhibitory action on glycogen synthase kinase-3 beta (GSK-3β), and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic-depressive psychosis and the like), alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors, or as immunopotentiators.

[2911] This application is based on patent application Nos. 2001-304707, 2001-26379, 2001-081238 and 2002-230581 filed in Japan, the contents of which are hereby incorporated by reference. 

What is claimed is:
 1. A dihydropyrazolopyridine compound of the formula (I):

wherein R⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: —COOR⁸ (wherein R⁸ is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)); R¹ and R² are the same or different and each is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl; R³ is (1) alkyl or haloalkyl, (2) cycloalkyl, (3) phenyl optionally having substituent(s), (4) aromatic heterocyclic group, (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent(s), or a group selected from the groups represented by the following formulas (II) and (III):

wherein R⁶ and R⁷ are each phenyl optionally having substituent(s) or an aromatic heterocyclic group, or R² and R³ in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s); R⁴ is alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), cyano or nitro; and R⁵ is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring; or phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: —(CR^(a)R^(b))_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R^(a) is hydrogen or alkyl, R^(b) is hydrogen or alkyl, R¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R¹² is hydrogen or alkyl, or R⁴ and R⁵ in conjunction may form a 5 or 6 membered ring optionally containing heteroatom(s), provided that when R⁰, R¹ and R² are each hydrogen, R⁴ is methoxycarbonyl and R⁵ is methyl, then R³ should not be phenyl, 2-chloropheny, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R⁵ is alkyl, then R⁴ is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 2. The dihydropyrazolopyridine compound of claim 1, wherein R⁰ is hydrogen, alkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: —COOR⁸ (wherein R⁸ is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)); R¹ and R² are the same or different and each is hydrogen, alkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl; R³ is (1) alkyl or haloalkyl, (2) cycloalkyl, (3) phenyl optionally having substituent(s), (4) aromatic heterocyclic group, (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent(s), or a group selected from the groups represented by the following formulas (II) and (III):

wherein R⁶ and R⁷ are each phenyl optionally having substituent(s) or an aromatic heterocyclic group, or R² and R³ in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s); R⁴ is alkoxycarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro; and R⁵ is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring, or R⁴ and R⁵ in conjunction may form a 5 or 6 membered ring optionally containing heteroatom(s), provided that when R⁰, R¹ and R² are each hydrogen, R⁴ is methoxycarbonyl and R⁵ is methyl, then R³ should not be phenyl, 2-chloropheny, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 3. The dihydropyrazolopyridine compound of claim 2, wherein R⁵ is alkyl having 2 to 8 carbon atoms, cycloalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, phenyl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 4. The dihydropyrazolopyridine compound of claim 2, wherein R¹ is hydrogen, alkyl, phenyl optionally having substituent(s), an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 5. The dihydropyrazolopyridine compound of claim 2, wherein R² is hydrogen or alkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 6. The dihydropyrazolopyridine compound of claim 2, wherein R³ is phenyl optionally having 1 to 3 substituent(s), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 7. The dihydropyrazolopyridine compound of claim 2, wherein R⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, cyano or nitro, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 8. The dihydropyrazolopyridine compound of claim 2, wherein R⁵ is alkyl having 2 to 4 carbon atoms, cyclopropyl, phenyl, thienyl or hydroxyalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 9. The dihydropyrazolopyridine compound of claim 2, wherein R² and R³ in conjunction form a ring containing sulfur atom and the ring is condensed with a benzene ring optionally having substituent(s), or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 10. The dihydropyrazolopyridine compound of claim 2, wherein R⁰ is hydrogen or a group of the formula: —COOR⁸ (wherein R⁸ is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)), or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 11. The dihydropyrazolopyridine compound of claim 2, which is selected from the group consisting of (32) ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (47) ethyl 4-(2-chloro-3-trifluoromethylphenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (66) ethyl 4,7-dihydro-4-(naphthalen-1-yl)-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (73) ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (87) ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (116) ethyl 4-(2,1,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (122) 4-(2,3-dichlorophenyl)-4,7-dihydro-5-nitro-6-propyl-2H-pyrazolo[3,4-b]pyridine, (140) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, (147) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine, (158) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-phenyl-2H-pyrazolo[3,4-b]pyridine, (171) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(thiophen-2-yl)-2H-pyrazolo[3,4-b]pyridine, (182) ethyl 4-(2-bromo-3-nitrophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (183) ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (189) 4-(2-bromo-3-nitrophenyl)-5-cyano-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, (205) ethyl 2-tert-butoxycarbonyl-4-(2-chlorophenyl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (240) ethyl 4-(2,1,3-benzoxadiazol-4-yl)-6-ethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate, (257) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-hydroxymethyl-2H-pyrazolo[3,4-b]pyridine, (260) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine, (264) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-isopropyl-2H-pyrazolo[3,4-b]pyridine, and (268) 4-(2-bromo-3-cyanophenyl)-5-cyano-6-cyclopropyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, a tautomer, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 12. The dihydropyrazolopyridine compound of claim 1, wherein R⁰ is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group optionally having substituent(s), phenylalkyl optionally having substituent(s), or a group of the formula: —COOR⁸ (wherein R⁸ is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)); R¹ is hydrogen; R² is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent(s), aromatic heterocyclic group or phenylalkyl; R³ is (1) alkyl or haloalkyl, (2) cycloalkyl, (3) phenyl optionally having substituent(s), (4) aromatic heterocyclic group, (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring, (6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s), or (7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s), which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent(s), or a group selected from the groups represented by the following formulas (II) and (III):

wherein R⁶ and R⁷ are each phenyl optionally having substituent(s) or an aromatic heterocyclic group, or R² and R³ in conjunction form a ring optionally containing heteroatom(s), wherein the ring may be fused with a benzene ring optionally having substituent(s); R⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group optionally having substituent(s), cyano or nitro; and R⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: —(CR^(a)R^(b))_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R^(a) is hydrogen or alkyl, R^(b) is hydrogen or alkyl, R¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R¹² is hydrogen or alkyl, provided that when R⁰, R¹ and R² are each hydrogen, R⁴ is methoxycarbonyl and R⁵ is methyl, then R³ should not be phenyl, 2-chlorophenyl, 3-nitrophenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl, and when R⁵ is alkyl, then R⁴ is not alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 13. The dihydropyrazolopyridine compound of claim 12, wherein R⁴ is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent(s), an aromatic heterocyclic group having substituent(s), cyano or nitro, and R⁵ is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent(s), a saturated 3 to 7 membered carbocyclic ring having substituent(s), alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula: —(CH₂)_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R¹¹ is hydrogen, alkyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylalkylsulfinyl, alkoxycarbonyl, phenoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, phenylcarbonyl or phenylalkylcarbonyl, and R¹² is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 14. The dihydropyrazolopyridine compound of claim 12 or 13, wherein R² is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 15. The dihydropyrazolopyridine compound of claim 12 or 13, wherein R³ is phenyl optionally having 1 to 3 substituent(s), naphthyl, 2,1,3-benzoxadiazol-4-yl or 3,4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 16. The dihydropyrazolopyridine compound of claim 12 or 13, wherein R⁴ is alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbonyl having 2 to 5 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, or alkylsulfinyl having 1 to 4 carbon atoms, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 17. The dihydropyrazolopyridine compound of claim 12 or 13, wherein R⁵ is a group of the formula: —(CH₂)_(n)NR¹¹R¹² wherein n is an integer of 1 to 4, R¹¹ is hydrogen, alkyl or alkoxycarbonyl and R¹² is hydrogen or alkyl, or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 18. The dihydropyrazolopyridine compound of claim 12 or 13, wherein R⁰ is hydrogen or a group of the formula: —COOR⁸ (wherein R⁸ is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)), or an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 19. The dihydropyrazolopyridine compound of claim 12 or 13, which is selected from the group consisting of (1002) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1003) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1011) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine, (1014) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine, (1023) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-(N,N-dimethylamino)cyclohexyl)-2H-pyrazolo[3,4-b]pyridine, (1027) 6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine, (1033) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1-ethylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1037) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1038) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1041) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridine, (1046) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(4-methylmorpholin-2-yl)-2H-pyrazolo[3,4-b]pyridine, (1048) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[3,4-b]-pyridine, (1051) 6-(1-acetylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (1052) 6-(1-benzoylpiperidin-4-yl)-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (1053) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1059) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(4-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine, (1062) 4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-6-(2-oxocyclohexan-1-yl)-2H-pyrazolo[3,4-b]pyridine, (1063) 6-acetylmethyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (1073) 5-cyano-4,7-dihydro-4-(2,3-(methylenedioxy)phenyl)-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine, (1075) 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-6-carboxylic acid phenylamide, (1078) 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(4-phenyl-piperazin-1-yl)methyl-2H-pyrazolo[3,4-b]pyridine, (1081) 6-acetyl-4-(2-bromo-3-cyanophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (1082) 6-acetyl-4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine, (1084) 4-(2-bromo-3-cyanophenyl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine, (1086) 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(pyrrolidin-3-yl)-2H-pyrazolo[3,4-b]pyridine, and (1087) 4-(2,1,3-benzoxadiazol-4-yl)-5-(pyridin-2-yl)-4,7-dihydro-6-propyl-2-pyrazolo[3,4-b]pyridine, a tautomer thereof, an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 20. A medicament comprising a dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
 21. A medicament comprising a dihydropyrazolopyridine compound of claim 12 or 13, an optically active form thereof, or a pharmaceutically acceptable salt thereof.
 22. A pharmaceutical composition comprising a dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.
 23. A pharmaceutical composition comprising a dihydropyrazolopyridine compound of claim 12 or 13, an optically active form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
 24. A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of claim 1 or 2, an optically active form thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof.
 25. A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of claim 12 or 13, an optically active form thereof and a pharmaceutically acceptable salt thereof.
 26. The medicament of claim 20 or 21, which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.
 27. The medicament of claim 20 or 21, which is used for prevention and/or treatment of a neurodegenerative disease.
 28. The medicament of claim 27, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic-depressive psychosis.
 29. The medicament of claim 20 or 21, which is used for prevention and/or treatment of diabetes and diabetic complications.
 30. The medicament of claim 20 or 21, which is used as an immunopotentiator.
 31. The medicament of claim 20 or 21, which is used for prevention and/or treatment of alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell lukemia or virus-induced tumors. 